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Principal InvestigatorInfrastructure to facilitate discovery of autism genesThe purpose of this project is to facilitate the discovery of the genes that contribute autism by maintaining an infrastructure which research groups studying the genetics of autism can work collaboratively. This will be accomplished through workshops, a Virtual Private Network, and access to a database that includes phenotype and genotype data from all participating groups.

Principal InvestigatorA California Population-Based Twin Study of AutismThis will address several fundamental questions: (1) What is the heritability of autism (2) What is the contribution of genetic factors to variation in symptom dimensions? (3) Is there a continuum between the quantitative neurocognitive traits and clinical disorder? (4) What proportion of the variance in the neurocognitive traits is accounted for by genetic and non-genetic factors?

Co-InvestigatorCenter for Integrating Ethics in Genetics Research(Cho)The goal of this project is to serve as a center of excellence in neurogenetics research, to develop a national model for bench, to bedside research ethics consultation, and to provide training opportunity in biomedical ethics.

Co-InvestigatorGene, Brain and Behavior in Turner Syndrome(Reiss)The primary objective of this project is to use advanced, multi-modal magnetic resonance imaging (MRI) techniques, analyses of X chromosome parent-of-origin and cognitive-behavioral assessment to elucidate the effects of monosomy and X-linked imprinting on neurodevelopment and neural function in a large cohort of young girls with Turner syndrome, pre-estrogen replacement.

Project DirectorProject F: Genomic Analysis in narcolepsy cataplexyThe goal of the project is to locate genes outside the HLA region that influence susceptibility to narcolepsy. In order to localize these genes we will carry out a linkage and association study in the most extensive world-wide collection of DNAs from well-characterized patients with narcolepsy and their families.

Abstract

Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status.A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC).Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group.This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype.

Abstract

A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and anomalous levels of cortisol secretion in this relation. Despite these associations, no study has assessed telomere length or its relation with HPA-axis activity in individuals at risk for depression, before the onset of disorder. In the present study, we assessed cortisol levels in response to a laboratory stressor and telomere length in 97 healthy young daughters of mothers either with recurrent episodes of depression (i.e., daughters at familial risk for depression) or with no history of psychopathology. We found that daughters of depressed mothers had shorter telomeres than did daughters of never-depressed mothers and, further, that shorter telomeres were associated with greater cortisol reactivity to stress. This study is the first to demonstrate that children at familial risk of developing MDD are characterized by accelerated biological aging, operationalized as shortened telomere length, before they had experienced an onset of depression; this may predispose them to develop not only MDD but also other age-related medical illnesses. It is critical, therefore, that we attempt to identify and distinguish genetic and environmental mechanisms that contribute to telomere shortening.

Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Abstract

Several genetic and environmental factors place youth offspring of parents with bipolar disorder (BD) at high risk for developing mood and anxiety disorders. Recent studies suggest that anxiety symptoms, even at subclinical levels, have been associated with an increased risk for developing BD. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the pathophysiology of both BD and anxiety disorders. We aimed to explore whether anxiety in BD offspring was associated with the BDNF Val66Met polymorphism. 64 BD offspring (mean age: 13.73 (S.D. 3.45) M = 30, F = 34) and 51 HC (mean age: 13.68 (S.D. 2.68) M = 23, F = 28) were compared on presence of the met allele and on scores from the Multidimensional Anxiety Scale for Children (MASC). To assess family function, we used the Family Adaptability and Cohesion Evaluation Scales (FACES-IV). The Baron & Kenny method was the statistical approach used to examine the moderating effects between variables. BD offspring showed higher levels of overall anxiety than did the HC group. BD offspring with the val/val genotype showed higher levels of anxiety than BD offspring with other genotypes. No significant levels of anxiety or its association with BDNF genotype were found in the HC group. BD offspring group showed significantly more family dysfunction when compared with the HC group and the family dysfunction moderated the association between the BDNF genotype and anxiety symptoms. This study demonstrated the potential interplay of three factors: BD offspring, anxiety symptoms and family dysfunction.

Abstract

Polysomnography (PSG) is the gold standard for the assessment of sleep, yet the extensive apparatus required for monitoring with PSG can be difficult to tolerate, particularly in children. Clinical populations, such as those with anxiety or tactile sensitivity, may have even greater difficulty tolerating the PSG equipment. This study evaluated an innovative protocol for obtaining full PSG in individuals diagnosed autism spectrum disorders (ASD) or developmental delay (DD), as well as typically developing controls (TD). The primary aim was to assess whether this protocol was equally successful for obtaining PSG between these groups.One hundred sixty-one individuals were recruited for participation; 93 with a diagnosis of ASD, 23 with a diagnosis of DD, and 45 TD. The participants and families were instructed on a procedure of systematic desensitization to the ambulatory PSG equipment; PSG was performed in the home of the participant.PSG was successfully attained in 144 (89.4%) participants. There was no difference in completion rate by diagnosis (p = 0.1), though younger age (p = 0.018) and duration of desensitization (p = 0.024) did predict PSG failure. Further, it was found that individuals with ASD took longer to desensitize to the equipment (16.08 d), than those with DD (8.04 d) or TD (0.98 d).Systematic desensitization to PSG equipment, in combination with PSG completed in the home, allows for individuals with ASD to be equally successful in completing PSG, though they do take longer to acclimate to the equipment.

Abstract

The serotonin transporter polymorphism short (s) allele is associated with heightened emotional reactivity and reduced emotion regulation, which increases vulnerability to depression and anxiety disorders. We investigated behavioral and neural markers of emotion regulation in community-dwelling older adults, contrasting s allele carriers and long allele homozygotes.Participants (N = 26) completed a face-word emotion conflict task during functional magnetic resonance imaging, in which facilitated regulation of emotion conflict was observed on face-word incongruent trials following another incongruent trial (i.e., emotional conflict adaptation).There were no differences between genetic groups in behavioral task performance or neural activation in postincongruent versus postcongruent trials. By contrast, connectivity between dorsal anterior cingulate cortex (ACC) and pregenual ACC, regions previously implicated in emotion conflict regulation, was impaired in s carriers for emotional conflict adaptation.This is the first demonstration of an association between serotonin transporter polymorphism and functional connectivity in older adults. Poor dorsal ACC-pregenual ACC connectivity in s carriers may be one route by which these individuals experience greater difficulty in implementing effective emotional regulation, which may contribute to their vulnerability for affective disorders.

Abstract

The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

Abstract

Multiple studies associate prenatal and perinatal complications with increased risks for autism spectrum disorders (ASDs). The objectives of this study were to utilize a twin study design to 1) Investigate whether shared gestational and perinatal factors increase concordance for ASDs in twins, 2) Determine whether individual neonatal factors are associated with the presence of ASDs in twins, and 3) Explore whether associated factors may influence males and females differently.Data from medical records and parent response questionnaires from 194 twin pairs, in which at least one twin had an ASD, were analyzed.Shared factors including parental age, prenatal use of medications, uterine bleeding, and prematurity did not increase concordance risks for ASDs in twins. Among the individual factors, respiratory distress demonstrated the strongest association with increased risk for ASDs in the group as a whole (OR 2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI 1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were associated with increased risks for ASDs in males, while jaundice was associated with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74).Perinatal factors associated with respiratory distress and other markers of hypoxia appear to increase risk for autism in a subgroup of twins. Future studies examining potential gender differences and additional prenatal, perinatal and postnatal environmental factors are required for elucidating the etiology of ASDs and suggesting new methods for treatment and prevention.

Abstract

There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.

Abstract

Brain-derived neurotrophic factor (BDNF) protein has been implicated in the pathophysiology of mood disorders, with early data suggesting that blood levels may vary by severity of mood symptoms. BDNF polymorphism, val66met, has also been implicated in mood disorders.Euthymic women with bipolar disorder (BD) (n=47) and healthy control women (n=26), ages 18-45, were clinically rated using the Montgomery-Asberg Depression Rating Scale (MADRS) and sampled for plasma BDNF concentration, with a subset undergoing genetic analysis for the val66met.BD and control groups did not differ on any demographic variables, nor in plasma BDNF levels or val66met polymorphism. Plasma BDNF concentration did not differ by val66met or BD subtype, nor was it correlated with age or illness duration. Within women with BD, lower plasma BDNF concentrations were significantly associated with higher MADRS scores, even after controlling for psychotropic medication use and illness duration.The sample was relatively small and exclusive to women, with further research needed to investigate the links between BDNF markers and mood symptom severity in both men and women.The study provides a gender-specific investigation of plasma BDNF levels and mood, and the results add further evidence of a significant interplay between BDNF markers and psychiatric symptomatology. Further, this association did not appear to be confounded by use of psychotropic medication. Studies with larger samples of both genders are needed to further delineate this relationship.

Abstract

Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

Abstract

Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.

Abstract

Phelan-McDermid syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of autism spectrum disorders (ASDs). PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N-methyl-D-aspartate (NMDA) receptors with fast deactivation kinetics. Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it.

Abstract

Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin) neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9) OR 0.77), ZNF365 (rs10995245 max P = 1.2 × 10(-11) OR 1.23), and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9) OR 0.75). Variants in the Human Leukocyte Antigen (HLA)- DQ region were associated with age of onset (rs7744020 P = 7.9×10(-9) beta -1.9 years) and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8 × 10(-10) OR 0.57). These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.

Abstract

To determine the genetic relationship between head circumference (HC) and Autism Spectrum Disorders (ASDs). Twin pairs with at least one twin with an ASD were assessed. HCs in affected and unaffected individuals were compared, as were HC correlations in monozygotic and dizygotic pairs. 404 subjects, ages 4-18, were included. 20 % of males and 27 % of females with an ASD had macrocephaly. Unaffected co-twins showed similar rates (16 % of males and 22 % of females). Statistical analysis revealed no significant difference in HCs between affected and unaffected twins. Twins with ASDs and unaffected co-twins have similar HCs and increased rates of macrocephaly. Correlations demonstrated partial inheritance of HCs. Thus, macrocephaly may represent an endophenotype in ASDs.

Abstract

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Abstract

There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (X(m)) and 17 from their father (X(p)). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with X(p) demonstrated thicker cortex than those with X(m) in the temporal regions bilaterally, while X(m) individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with X(p). These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome.

Abstract

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Abstract

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.

Abstract

Resilience is proposed as a significant component of successful aging. Young adult carriers of the Serotonin Transporter Polymorphism (5-HTTLPR) short(s) allele appear to have reduced resilience to stress. We examined whether the presence of the short allele was associated with poorer emotional resilience in older adults.In a cross-sectional study of 99 healthy, community-dwelling, older adults, we determined 5-HTTLPR genotype status and administered the Connor-Davidson Resilience Scale and self-reported measures of successful aging, cognition, and health.There was no significant association between the 5-HTTLPR s allele and resilience. S allele carriers had worse cognition and self-report ratings of successful aging.These findings suggest that the impact of the 5-HTTLPR s allele on stress-related outcomes may attenuate with older age. However, s allele status appears to be a biomarker of poorer self-rated successful aging, and cognitive performance in older adults.

Abstract

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.

Abstract

Recent evidence suggests that the cognitive and social manifestations associated with Turner syndrome (TS) might be influenced by epigenetic factors in the form of genomic imprinting. However, due to small and heterogeneous samples, inconsistent results have emerged from these studies.The objective of this prospective study was to establish the impact of genomic imprinting on neurocognitive abilities and social functioning in young girls with TS.An extensive battery of neuropsychological assessments was administered to 65 children with TS who had never been exposed to estrogen treatment, 24 of whom had an X-chromosome from paternal origin (Xpat) and 41 from maternal origin (Xmat).The Wechsler scales of intelligence, the Motor-Free Visual Spatial test-3, the Wide Range Assessment of Visual Motor Ability, and the attention/executive domain of the NEPSY were used to assess cognitive abilities. Social functioning was assessed with the Social Responsiveness Scale and the Behavior Assessment System for Children-2.Results showed that although individuals with Xpat obtained lower scores than their counterparts with Xmat on most cognitive and social measures, only the Perceptual Reasoning Index of the intelligence scale yielded significant differences after correction for multiple comparisons.Overall, these results suggest that although some aspects of the neuropsychological profile of TS may be influenced by epigenetic factors, the sociocognitive phenotype associated with the disorder is not modulated by genomic imprinting.

Abstract

Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.

Abstract

Posttraumatic stress disorder (PTSD) is associated with structural and functional compromise of the anterior cingulate cortex (ACC), which may in turn be associated with impairment of its ability to regulate the amygdala. The Val158Met polymorphism in the catechol-O-methyltransferase gene, which substantially influences dopamine inactivation in the frontal lobe in general and in ACC in particular, may moderate ACC integrity in PTSD.We tested this hypothesis in a sample of Vietnam and Persian Gulf War veterans who experienced substantial military operational stress, including 51 who met criteria for PTSD and 48 matched controls who did not.Participants with PTSD were previously reported to have smaller ACC volumes than controls in this sample. A novel repeated-measures analysis of variance was conducted with PTSD diagnosis, Val158Met genotype, and their interaction predicting left and right ACC volume. Genotype was not directly related to ACC volume, but it did significantly interact with the PTSD diagnosis. The difference in ACC volume between the participants without PTSD and participants with PTSD was greater among individuals homozygous for the Val allele than among carriers of the Met allele. This finding was driven largely by the right ACC. Analyses of Caucasian-only, non-Caucasian-only, and male-only subsamples indicated similar patterns.Our findings suggest Val158Met genotype moderates the effect of PTSD-related processes on right ACC volume.

Abstract

Insulin resistance (IR) is the main pathological condition underlying vascular disorders, such as diabetes and cardiovascular disease, which are well established risk factors for cognitive decline and Alzheimer disease (AD). Hippocampal atrophy has been associated with cognitive decline, but little is known about the influence of IR on hippocampus integrity in non-diabetic, cognitively intact individuals. Herein, 50 women ages 50-65, current users of hormone therapy, underwent magnetic resonance imaging, cognitive testing, and homeostatic assessment of insulin resistance (HOMA-IR), as part of a longitudinal study examining brain structure and function in postmenopausal women at risk for AD. Results demonstrated a significant negative relationship between HOMA-IR and right and total hippocampal volume, overall cognitive performance, and selective tests of verbal and non-verbal memory. The main effect of HOMA-IR on brain structure and cognition was not altered by the presence of APOE-?4 allele or by reproductive history, such as duration of endogenous and exogenous estrogen exposure. These results suggest that IR in middle-aged individuals at risk for AD may be biomarker for dementia risk.

Abstract

Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O'Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.

Abstract

Characterization of developmental trajectories across the lifespan is integral to understanding the prodromal course of many neuropsychiatric illnesses and the significant risk factors for disease onset or unfavorable outcomes. However, the standard experimental designs used in psychiatric research are not ideal for this purpose. The authors review the limitations of the most commonly employed designs in studies that make developmental or lifespan inferences in psychiatry: cross-sectional, single-cohort longitudinal, and unstructured multicohort longitudinal designs. Cross-sectional studies completely confound within- and between-subject sources of variation and hence rely on the presence of parallel trajectories and negligible sampling and age cohort differences for making valid developmental inferences. Delineating trajectories of within-individual change over substantial periods of time requires data covering long age spans that often cannot be covered using single-cohort longitudinal designs. Unstructured multicohort longitudinal designs are a commonly used alternative that can cover a longer age span in a shorter interval than necessary for a single-cohort design. However, the impact of cohort and sampling effects is often minimized or ignored in unstructured multicohort longitudinal designs. The authors propose that structured multicohort longitudinal designs are a particularly viable and underutilized class of designs in psychiatry that represents a significant improvement over cross-sectional designs and unstructured multicohort longitudinal designs for making developmental inferences while being more practical to implement than single-cohort longitudinal designs. As an example of this approach, the authors analyze changes in entorhinal cortex thickness in Alzheimer's disease in relation to APOE-?4 genotype.

Abstract

One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes.One week of ad libitum ambulatory sleep data collection.At-home collection of sleep data and in-laboratory questionnaire.Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set.Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined.Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance.It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

Abstract

The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well.

Abstract

Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.

Abstract

The nonapeptide oxytocin and its receptor have been implicated in the regulation of mammalian social behavior and stress physiology. Evidence is accumulating that the quality of the parental environment is associated with oxytocin biology in children. The present study was designed to examine the interaction of the single nucleotide polymorphism (SNP) rs2254298 within the oxytocin receptor (OXTR) gene and quality of parental environment in predicting children's psychosocial functioning. More specifically, in a sample of 92 Caucasian adolescent girls (9-14 years old), we examined whether adverse parental environment, operationalized as mothers' history of recurrent major depressive disorder, interacts with the rs2254298 SNP on the OXTR gene to predict daughters' symptoms of depression and anxiety. Caucasian girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety. These findings highlight the potential importance of this OXTR gene polymorphism in the etiology of depression and anxiety disorders.

Abstract

Autism spectrum disorder (ASD) is characterised by impairments in social communication and by a pattern of repetitive behaviours, with learning disability (LD) typically seen in up to 70% of cases. A recent study using the PPL statistical framework identified a novel region of genetic linkage on chromosome 16q21 that is limited to ASD families with LD.In this study, two families with autism and/or LD are described which harbour rare >1.6 Mb microdeletions located within this linkage region. The deletion breakpoints are mapped at base-pair resolution and segregation analysis is performed using a combination of 1M single nucleotide polymorphism (SNP) technology, array comparative genomic hybridisation (CGH), long-range PCR, and Sanger sequencing. The frequency of similar genomic variants in control subjects is determined through analysis of published SNP array data. Expression of CDH8, the only gene disrupted by these microdeletions, is assessed using reverse transcriptase PCR and in situ hybridisation analysis of 9 week human embryos.The deletion of chr16: 60?025?584-61?667?839 was transmitted to three of three boys with autism and LD and none of four unaffected siblings, from their unaffected mother. In a second family, an overlapping deletion of chr16: 58?724?527-60?547?472 was transmitted to an individual with severe LD from his father with moderate LD. No copy number variations (CNVs) disrupting CDH8 were observed in 5023 controls. Expression analysis indicates that the two CDH8 isoforms are present in the developing human cortex.Rare familial 16q21 microdeletions and expression analysis implicate CDH8 in susceptibility to autism and LD.

Abstract

Diffusion tensor imaging is widely used to evaluate the development of white matter. Information about how alterations in major neurotransmitter systems, such as the dopamine (DA) system, influence this development in healthy children, however, is lacking. Catechol-O-metyltransferase (COMT) is the major enzyme responsible for DA degradation in prefrontal brain structures, for which there is a corresponding genetic polymorphism (val158met) that confers either a more or less efficient version of this enzyme. The result of this common genetic variation is that children may have more or less available synaptic DA in prefrontal brain regions. In the present study we examined the relation between diffusion properties of frontal white matter structures and the COMT val158met polymorphism in 40 children ages 9-15. We found that the val allele was associated with significantly elevated fractional anisotropy values and reduced axial and radial diffusivities. These results indicate that the development of white matter in healthy children is related to COMT genotype and that alterations in white matter may be related to the differential availability of prefrontal DA. This investigation paves the way for further studies of how common functional variants in the genome might influence the development of brain white matter.

Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Abstract

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Abstract

The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.

Abstract

Neuritin 1 (NRN1), an activity-regulated gene with multiple roles in neurodevelopment and synaptic plasticity, is located within the 6p24-p25 interval on chromosome 6, previously identified as linked to a subtype of schizophrenia (SZ) characterized by pervasive cognitive deficit (CD). We have tested the effect of NRN1 sequence variation on susceptibility to SZ and on general cognitive ability in patients and non-psychiatric control subjects by re-sequencing the coding regions of NRN1 and its flanking sequences, and genotyping 19 single-nucleotide polymorphisms (SNPs) in 336 SZ patients and 172 healthy control individuals. All participants completed comprehensive neurocognitive assessment, including tests estimating premorbid/prior IQ and current IQ. Logistic regression analyses found no significant association for any of the 19 SNPs with SZ or its CD subtype. However, linear regression analysis gave significant association (P = 0.024 and P = 0.027 after correction for multiple testing) for polymorphisms rs1475157 and rs9405890 with current IQ in the patient group. In SZ, the rs1475157-rs9405890 haplotypes revealed a highly significant association with the abstraction component of current ("fluid") intelligence (P = 0.0014), and with percentage loss of IQ points between premorbid and current intelligence (P = 0.0041). Results in the control group were not significant after correction. This is the first analysis of association between variation in NRN1 and SZ. The findings suggest a role of NRN1 as a modifier of cognitive functioning in SZ, with implications for future research into the impact of the environment on the development and maintenance of "fluid" intelligence.

Abstract

Autism is a neurodevelopmental disorder with a strong genetic background that has been suggested to be associated with a susceptibility gene, engrailed homeobox 2(EN2), which maps to chromosome 7q36. Our study was aimed to explore the association between EN2 intronic single nucleotide polymorphisms (SNPs) with autism in an ethnic Han Chinese population.A total of 193 autism cases and 309 controls were recruited. Five SNPs including rs3824068, rs3824067, rs1861972, rs1861973 and rs3830031 in the intron 1 region were genotyped by using the TaqMan SNP assay.Both the allelic frequencies and genotype distribution of the EN2 intronic SNPs were found to have statistically significant differences between cases and controls, except rs1861972, rs3024067 and rs3824068. According to the constructed linkage disequilibrium plot using genotype data, it was suggested that further haplotypic analyses can be performed on rs3824068, rs1861972 and rs1861973. After completed analyses by the Unphased and Phase programs and logistic regression analysis, one 2-marker haplotype A-C (beta = -2.897; p = 0.013; OR = 0.055) and one 3-marker haplotype G-A-C (beta = -0.491; p = 0.015; OR = 0.612) were identified that were plausibly associated with autism in the ethnic Chinese population.The haplotype A-C of rs1861972 and rs1861973 is the core element of the observed haplotype association in this study, which plays a role as a protective factor against autism; in addition, the haplotype G-A-C is less frequent in male cases compared to controls (38.64 vs. 52.51%), which plausibly modulate disease vulnerability to autism. However, further evidence of the haplotype association of EN2 intronic SNPs and uncertain transcription factor interaction is warranted for further clarification.

Abstract

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Abstract

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10(-21), 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

Abstract

We report the results of follow-up analyses of 12 genomic regions showing evidence of linkage in a genome-wide scan (GWS) of Gypsy families with bipolar affective disorder (BPAD). The Gypsies are a young founder population comprising multiple genetically differentiated sub-isolates with strong founder effect and limited genetic diversity. The BPAD families belong to a single sub-isolate and are connected by numerous inter-marriages, resulting in a super-pedigree with 181 members. We aimed to re-assess the positive GWS findings and search for evidence of a founder susceptibility allele after the addition of newly recruited subjects, some changes in diagnostic assignment, and the use of denser genetic maps. Linkage analysis was conducted with SimWalk2, accommodating the full complexity of pedigree structure and using a conservative narrow phenotype definition (BPAD only). Six regions were rejected, while 1p36, 13q31, 17p11, 17q21, 6q24, and 4q31 produced nominally significant results in both the individual families and the super-pedigree. Haplotypes were reconstructed and joint tests for linkage and association were done for the most promising regions. No common ancestral haplotype was identified by sequencing a strong positional and functional candidate gene (GRM1) and additional STR genotyping in the top GWS region, 6q24. The best supported region was a 12 cM interval on 4q31, also implicated in previous studies, where we obtained significant results in the super-pedigree using both SimWalk2 (P = 0.004) and joint Pseudomarker analysis of linkage and linkage disequilibrium (P = 0.000056). The size of the region and the characteristics of the Gypsy population make it suitable for LD mapping.

The seasonal relationship between assault and homicide in England and WalesINJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJUREDRock, D. J., Judd, K., Hallmayer, J. F.2008; 39 (9): 1047-1053

Abstract

Investigating the seasonal asymmetry of violent behaviour has a long history. Despite this, there still remains considerable debate about the nature and aetiology of this phenomenon. Reports on homicide, for example, are mixed: some have found homicide seasonality but most have not. In contrast, all published studies on assault report that this behaviour is seasonal. Moreover, only two studies, both using US data, have examined the seasonal variation of assault and homicide in the same population over the same period of time. One group found assault was seasonal but homicide was not, whilst the other found, overall, that both homicide and assault were seasonal. This first of these findings seems paradoxical, in that there is no seasonal variation in injury related deaths (i.e. homicides), despite the antecedent behaviour (i.e. assaults) having a seasonal pattern of occurrence. We examined the seasonal variation in homicide and assault in UK and found a similar result. Furthermore, our findings are not easily understandable using conventional social models of seasonal behaviour and we suggest biologically mediated seasonal variation in the capacity of equally injured individuals to survive trauma may also play a role, which should be investigated further.

Abstract

Inflammatory changes are a prominent feature of brains affected by Alzheimer's disease (AD). Activated glial cells release inflammatory cytokines which modulate the neurodegenerative process. These cytokines are encoded by genes representing several interleukins and TNFA, which are associated with AD. The gene coding for HLA-B associated transcript 1 (BAT1) lies adjacent to TNFA in the central major histocompatibility complex (MHC). BAT1, a member of the DEAD-box family of RNA helicases, appears to regulate the production of inflammatory cytokines associated with AD pathology. In the current study TNFA and BAT1 promoter polymorphisms were analysed in AD and control cases and BAT1 mRNA levels were investigated in brain tissue from AD and control cases.Genotyping was performed for polymorphisms at positions -850 and -308 in the proximal promoter of TNFA and position -22 in the promoter of BAT1. These were investigated singly or in haplotypic association in a cohort of Australian AD patients with AD stratified on the basis of their APOE epsilon4 genotype. Semi-quantitative RT-PCR was also performed for BAT1 from RNA isolated from brain tissue from AD and control cases.APOE epsilon4 was associated with an independent increase in risk for AD in individuals with TNFA -850*2, while carriage of BAT1 -22*2 reduced the risk for AD, independent of APOE epsilon4 genotype. Semi-quantitative mRNA analysis in human brain tissue showed elevated levels of BAT1 mRNA in frontal cortex of AD cases.These findings lend support to the application of TNFA and BAT1 polymorphisms in early diagnosis or risk assessment strategies for AD and suggest a potential role for BAT1 in the regulation of inflammatory reactions in AD pathology.

Abstract

Recent evidence indicates that individuals who are homozygous for the short (s) allele in the promoter region of the serotonin transporter gene have higher rates of depression and other psychiatric disorders as a function of exposure to increasing levels of stressful life events than do individuals who have one or two copies of the long (l) allele. Despite the reliability of this association, the mechanism by which this polymorphism confers risk for psychopathology in the presence of stress is not understood. This study was designed to examine the formulation that individuals who are homozygous for the s allele are characterized by a greater biological reactivity to stress than are their counterparts who have one or two copies of the l allele.Girls at high (n = 25) and low (n = 42) risk for depression by virtue of the presence or absence of a family history of this disorder were genotyped and exposed to a standardized laboratory stress task. Cortisol levels were assessed before the stressor, after the stressor, and during an extended recovery period.Girls who were homozygous for the s allele produced higher and more prolonged levels of cortisol in response to the stressor than did girls with an l allele.These findings indicate that the 5-HTTLPR polymorphism is associated with biological stress reactivity, which may increase susceptibility to depression in the face of stressful life events.

The Seasonal Risk for Deliberate Self-Harm Determined by Place of Birth, but Occurrence Determined by Place of ResidenceCRISIS-THE JOURNAL OF CRISIS INTERVENTION AND SUICIDE PREVENTIONRock, D. J., Hallmayer, J. F.2008; 29 (4): 191-201

Abstract

Groups at seasonal risk for deliberate self-harm (DSH) vary according to their geographic location. It is unknown, however, if seasonal risk factors for DSH are associated with place of birth or place of residence as these are confounded in all studies to date. In order to disaggregate place of birth from place of residence we examined general and seasonal risk factors for DSH in three different population birth groups living in Western Australia: Australian Aborigines, Australian born non-Aborigines, and UK migrants. We found Aborigines are at much higher general risk for DSH than non-Aborigines, but are not at seasonal risk, whereas non-Aboriginal Australians and UK migrants are. For UK migrants, this is only found for females. For all groups at seasonal risk this peaks during the austral (southern hemisphere) spring/summer. Furthermore, non-Aboriginal Australians and UK migrants show a consistent pattern of increased case fatality with increasing age. In contrast, case fatality does not increase with age among Australian Aborigines. Overall, despite living in the same environment, the three birth groups show different patterns of seasonal risk for DSH. In particular, the sex difference found between UK migrants and non-Aboriginal Australian birth groups suggests that predisposition toward seasonal risk for DSH is established early in life, but when present this is expressed according to local conditions.

Abstract

The s allele variant of the serotonin transporter gene (5-HTT) has recently been observed to moderate the relationship of stress to depression and anxiety. To date no study has considered interactive effects of 5-HTT genotype, stress and hypothalamic-pituitary-adrenal (HPA) function on cognition in healthy, older adults, which may reflect developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism. We investigated whether 5-HTT genotype interacts with cumulative life stress and HPA-axis measures of waking and diurnal cortisol slope to impact cognition in 154 non-depressed, older adults. Structural images of hippocampal volume were acquired on a subsample of 56 participants. The 5-HTT s allele was associated with both significantly lower delayed recall and higher waking cortisol levels. Presence of the s allele interacted with higher waking cortisol to negatively impact memory. We also observed a significant interaction of higher waking cortisol and the s allele on lower hippocampal volume. Smaller hippocampi and higher cortisol were associated with lower delayed recall only in s allele carriers. No impact or interactions of cumulative life stress with 5-HTT or cortisol were observed. This is the first investigation to identify an association of the 5-HTT s allele with poorer memory function in older adults. The interactive effects of the s allele and waking cortisol levels on reduced hippocampal volume and lower memory suggest that the negative effect of the serotonin polymorphism on memory is mediated by the HPA axis. Further, given the significant association of the s allele with higher waking cortisol in our investigation, future studies may be needed to evaluate the impact of the serotonin transporter polymorphism on any neuropsychiatric or behavioral outcome which is influenced by HPA axis function in older adults.

Abstract

22q11.2 deletion syndrome (22q11.2DS) is a well-known genetic risk factor for schizophrenia. The catechol-O-methyltransferase (COMT) gene falls within the 22q11.2 minimal critical region of the deletion. Brain activity, as measured by functional magnetic resonance imaging (fMRI) during a Go/NoGo, response inhibition task was assessed in adolescents with 22q11.2DS (n = 13), typically developing (TD) controls (n = 14), and controls with developmental disability (DD, n = 9). Subjects with 22q11.2DS were also genotyped for the COMT Met/Val polymorphism. Groups did not differ on task performance. However, compared to both control groups, the 22q11.2DS group showed greater brain activation within left parietal regions. Comparison of brain activation between 22q11.2DS Met and Val subgroups revealed significantly increased activation (Met>Val) in the cingulate but not the dorsolateral prefrontal cortex. These preliminary findings suggest that adolescents with 22q11.2DS compensate for executive dysfunction via recruitment of parietal regions. Further, the COMT Met subgroup of 22q11.2DS may recruit additional cingulate activation for tasks requiring attention and inhibition. 22q11.2DS is a unique model for learning about the deleterious effects of decreased dosage of the COMT gene on brain function.

Abstract

The etiology of autism is complex, consisting of unknown genetic and environmental factors. Previous studies have revealed that maternal age is increased in autism compared to controls, making it a possible risk factor. This study examined the effects of maternal age on autism severity using IQ as a measure of cognitive severity and selected subtests of the Child Behavior Checklist (CBCL) as measures of social severity. A sample of 154 subjects with autism spectrum disorders was obtained from the Stanford Neuropsychiatry/Pervasive Developmental Disorder (PDD) clinic. Results indicate that there is no relationship between IQ or selected CBCL subtests and maternal age, suggesting that maternal age does not influence the severity of autism as measured by these indicators.

Abstract

Children with autistic disorder (AD), mixed receptive-expressive language disorder (RELD), or developmental coordination disorder (DCD) have impairments in common. We assess which abilities differentiate the disorders. Children aged 3-13 years diagnosed with AD (n = 30), RELD (n = 30), or DCD (n = 22) were tested on measures of language, intelligence, social cognition, motor coordination, and executive functioning. Results indicate that the AD and DCD groups have poorer fine and gross motor coordination and better response inhibition than the RELD group. The AD and DCD groups differ in fine and gross motor coordination, emotion understanding, and theory of mind scores (AD always lower), but discriminant function analysis yielded a non-significant function and more classification errors for these groups. In terms of ability scores, the AD and DCD groups appear to differ more in severity than in kind.

Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Abstract

Discoveries in the field of neuroscience are a natural source of discourse among scientists and have long been disseminated to the public. Historically, as news of findings has travelled between communities, it has elicited both expected and unusual reactions. What scientific landmarks promote discourse within the professional community? Do the same findings achieve a place in the public eye? How does the media choose what is newsworthy, and why does the public react the way it does? Drawing on examples of past challenges at the crossroads of neuroscience and society and on a case study of trends in one neurogenetic disease, autism, we explore the dialectical forces interacting in scientific and public discourse.

Abstract

A common polymorphism (Val158Met) in the gene encoding for the catechol-O-methyltransferase (COMT) enzyme has been associated with differences in prefrontal cognitive function in schizophrenic patients and healthy adults. While several studies indicate that the Met allele is associated with better performance on measures of executive function, working memory and verbal fluency, results have been inconsistent. Furthermore, fewer studies have investigated this relationship in older adults, a group known to experience impairments in prefrontal cognitive functions. Additionally, findings vary according to the gender distribution of study participants. We examined whether COMT genotype interacted with gender to impact cognition in a cohort of 163 healthy, older adults. Memory, verbal ability and areas of prefrontal cognitive function, including attention, speed-of-processing, and executive function, were assessed. We found no significant association between COMT genotype and any cognitive measure. However, gender interacted with COMT genotype to impact cognitive performance. Males homozygous for the Val allele performed better than both the Val/Met and Met/Met groups on measures of delayed recall. Heterozygous women performed better than their homozygous counterparts on the measure of verbal ability. These findings suggest that gender may be an important variable in consideration of the impact of COMT on cognition. Further, when gender is taken into consideration, any negative impact of COMT genotype may extend to cognitive domains other than those associated with prefrontal regions.

Abstract

Antidepressant-induced mania (AIM) has been described in bipolar disorder (BD) and has been associated with the short-allele of the serotonin transporter gene (5-HTT). We wished to investigate the frequency of and risk factors for AIM in pediatric patients with or at high risk for BD.Fifty-two children and adolescents (30 with BD and 22 with subthreshold manic symptoms, 15.1 +/- 3.4 years old), all with a parent with BD, were interviewed with their parents for manic/depressive symptoms occurring before and after past antidepressant treatment. The 47 subjects with serotonin reuptake inhibitor (SSRI) exposure were genotyped for the 5-HTT polymorphism.Fifty percent of subjects were AIM+ and 25.5% had new onset of suicidal ideation. The AIM+ and AIM- groups did not differ significantly in relation to allele (p = .36) or genotype (p = .53) frequencies of the 5-HTT polymorphism. The AIM+ subjects were more likely to have more comorbidities (3.2 vs. 2.4; p = .02) and be BD type I (p = .04) than AIM- subjects.Youth with or at high risk for BD may be particularly vulnerable to SSRI AIM and thus should be monitored if given SSRIs. In this preliminary study, we did not find that the 5-HTT polymorphism significantly influenced vulnerability to AIM.

Abstract

Delineation of a cognitive endophenotype for autism is useful both for exploring the genetic mechanisms underlying the disorder and for identifying which cognitive traits may be primary to it. This study investigated whether first-degree relatives of individuals with autism spectrum disorders (ASDs) demonstrate a specific profile of performance on a range of components of executive function (EF), to determine whether EF deficits represent possible endophenotypes for autism. Parents and siblings of ASD and control probands were tested on EF tasks measuring planning, set-shifting, inhibition and generativity. ASD parents showed poorer performance than control parents on a test of ideational fluency or generativity, and ASD fathers demonstrated a weakness in set-shifting to a previously irrelevant dimension. ASD siblings revealed a mild reduction in ideational fluency and a weakness in non-verbal generativity when compared with control siblings. Neither ASD parents nor siblings displayed significant difficulties with planning or inhibition. These results indicated that the broad autism phenotype may not be characterized primarily by impairments in planning and cognitive flexibility, as had been previously proposed. Weaknesses in generativity emerged as stronger potential endophenotypes in this study, suggesting that this aspect of EF should play a central role in cognitive theories of autism. However, discrepancies in the EF profile demonstrated by parents and siblings suggest that factors related to age or parental responsibility may affect the precise pattern of deficits observed.

Abstract

Linkage studies in schizophrenia have identified a candidate region on chromosome 10p14-11 as reported for several independent samples. We investigated association of DNA sequence variants in a plausible candidate gene located in this region, the gene for phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A), in a sample of 65 sib-pair families for which linkage had been reported. Evidence for association was obtained for 15 polymorphisms spanning 73.6 kb in the genomic region of the gene between intron 4 and the 3' untranslated region, a region with high degree of linkage disequilibrium. Single nucleotide polymorphism (SNP) rs10828317 located in exon 7 and causing a non-synonymous amino-acid exchange (asparagine/serine) produced a P-value of 0.001 (experiment-wide significance level 0.00275) for over-transmission of the major allele coding for serine, analysed by transmission disequilibrium test using FAMHAP. Association of this SNP with schizophrenia has been also described in a sample of 273 Dutch schizophrenic patients and 580 controls (P=0.0004). PIP5K2A is involved in the biosynthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), one of the key metabolic crossroads in phosphoinositide signalling. PI(4,5)P2 plays a role in membrane transduction of neurotransmitter signals as well as in intracellular signalling, pathways that may be impaired in schizophrenia.

Abstract

Non-autistic relatives of people with autistic disorder have an increased risk of social and communicative difficulties: this is known as the "broad phenotype." Better methods for characterizing the broad phenotype are needed to facilitate identification of risk genes for autism. 29 siblings of 20 children with autistic disorder, 13 siblings of 9 children with PDDNOS, and 46 typically developing control children from 26 families were assessed by parental report using the Children's Communication Checklist-2 (CCC-2). Groups were matched on age and IQ and siblings with autism were excluded. Group mean scores on the CCC-2 differed on only one subscale, syntax. However, siblings of children with autism or PDDNOS were over-represented in the tails of the distributions of several scales, and 10 (24%) scored more than 2 SD below the control mean on a total score based on all 10 subscales. Only two of these 10 children scored above threshold on one or more scales of the Autism Diagnostic Interview-Revised (ADI-R). Children with abnormal scores on the CCC-2 total were characterized by low-verbal IQ and their fathers tended to score high on the social and communication scales of the Autism Quotient, a measure of the broad phenotype in adults. The CCC-2 shows promise as a quick screening device for the broad phenotype in non-autistic siblings of children with autism.

Abstract

Despite implicating the same biological systems, the relationship between suicide seasonality and season-of-birth has not been examined previously. The purpose of this study was to investigate the interaction between season-of-birth and the seasonality of suicidal behaviour. All adult suicides (N = 2923) and deliberate self harm (DSH) hospitalizations (N = 33321) in Western Australia (1970-96) were examined. A variable population at risk approach was used to determine season-of-birth. Seasonality was established by spectral analysis. We found that DSH has a significant season-of-birth (p = 0.047) and seasonality of occurrence, both peaking in spring. Individuals born in the 90 days centred on the peak birth period, however, show no DSH seasonality. In contrast, suicide has no season-of-birth (p = 0.53). We also found a season-of-birth effect among the DSH group that eliminates any seasonality of DSH among the high-risk by birth group. Further work is needed to identify the possible biological and environmental determinants of this interaction.

Abstract

Evidence from both linkage analyses and association-based analyses has implicated Apoliprotein E (ApoE) as a disease susceptibility locus for obstructive sleep apnea. To further assess the putative role of ApoE in sleep apnea, we performed genotyping, association, and linkage analyses in a cohort assembled to investigate the genetic epidemiology of sleep apnea. Among a subset of the Caucasian families, ten microsatellites, spanning 20 cM, were genotyped in a region near ApoE on chromosome 19 where previous suggestive linkage had been demonstrated using a 9.1-cM genome-wide scan. Haseman-Elston regression analysis, conducted with these fine mapping markers (n=196 sibling pairs, 56 families), showed evidence for linkage to marker AFM210yg9 (p=0.00034), which was increased over that observed with the original scan. ApoE genotyping also was performed on a larger set of data (n=1,211 from 271 families, ages 3-85 years) from the cohort with available DNA. To determine whether the ApoE genotype explains the linkage peak, we included the ApoE genotype as a covariate in regression models. Inclusion of ApoE E2 allele as a covariate reduced the regression coefficient by 18%, suggesting that ApoE does not substantively explain the linkage signal. Finally, we repeated an association-based analysis in the larger sample of 1,211 individuals, and observed a higher prevalence of sleep apnea among individuals with the ApoE E2 allele. Overall, the evidence suggests that there is a disease susceptibility locus for obstructive sleep apnea in the region of ApoE, but ApoE itself is unlikely to be the causative locus.

Abstract

We propose that stronger than usual correlations between abilities indicate which cognitive processes are impaired in autism. Study 1 compared partial correlations (controlling age) between intelligence and social cognition in children with autism (n = 18), mental retardation (MR; n = 34), or no psychological disorder (n = 37). Correlations were stronger in the autism group. Study 2 compared correlations between measures of perceptual organization and verbal comprehension, receptive and expressive language, fine and gross motor coordination, and theory of mind, emotion recognition, and emotion understanding abilities in children with autism (n = 30) or MR (n = 24) and in a large representative sample of children (n = 449). Results indicate that autism is marked by stronger correlations between all ability domains, and MR is marked by stronger correlations between motor coordination tasks and other ability measures.

Abstract

A number of differences exist between the seasonality of suicide and suicidal behaviour. Case fatality is one index of the relationship between these phenomena. The purpose of this study was to use contemporaneous data to examine the impact of case fatality on the seasonality of suicidal behaviour. All deliberate self-harm (ICD9 E950-58) hospitalisations (DSH) and deaths (suicide) for 1984-93 were extracted from the Western Australia case register (N=22 883). Case fatality was calculated by method of suicide. Data were arranged in time series by standardised month according to case fatality; sex and age and analysed using spectral analysis. We found that DSH involving low case fatal methods is seasonal with a spring peak (95% confidence interval). The explained variance of the seasonal rhythm increases with age. Suicide involving high case fatal methods is not seasonal. The increase in DSH seasonality with age may be related to a parallel increase in case fatality.

Abstract

A novel phenotyping strategy in schizophrenia, targeting different neurocognitive domains, neurobehavioral features, and selected personality traits, has allowed us to identify a homogeneous familial subtype of the disease, characterized by pervasive neurocognitive deficit. Our genome scan data indicate that this subtype, which accounts for up to 50% of our sample, has a distinct genetic basis and explains linkage to chromosome 6p24 reported previously. If representative of other populations, the ratio of schizophrenia subtypes observed in our families could have a profound impact on sample heterogeneity and on the power of genetic studies to detect linkage and association. Our proposed abbreviated battery of tests should facilitate phenotype characterization for future genetic analyses and allow a focus on a crisply defined schizophrenia subtype, thus promoting a more informed search for susceptibility genes.

Abstract

Given the high level of comorbidity of attention deficit hyperactivity disorder (ADHD) and developmental coordination disorder (DCD), deficits in executive function (EF), shown to be present in children with ADHD, may also be implicated in the motor coordination deficits of children with DCD. The aim of this study was to explore the relationship between EF and motor ability. A sample of 238 children, 121 girls and 117 boys, aged between 6 and 15 years was recruited for this project. Motor ability was assessed using the McCarron Assessment of Neuromuscular Development (MAND), level of inattention using the Child Behavior Checklist (CBCL), and Verbal IQ (VIQ) was estimated using subtests of the WISC-III. A reaction time task and three EF tasks measuring response inhibition, working memory and the ability to plan and respond to goal-directed tasks were administered. It was found that motor ability significantly accounted for variance in tasks measuring speed of performance, whereas inattention appeared to influence performance variability. Despite past evidence linking poor motor ability with inattention, there was little overlap in the processes that are affected in children with motor coordination or attention problems.

Abstract

The concept of the 'broad phenotype' of autism refers to the finding that relatives of people with autism often have mild forms of autistic-like characteristics, such as social and communicative difficulties. This study used the Autism Spectrum Quotient (AQ), a questionnaire devised to assess features of the broad phenotype in adults, with parents of people with autism, to see whether they would be more likely to obtain extreme scores than a control group.The AQ was administered to parents of 69 people with an autism spectrum disorder and parents of 52 controls.On two of the five subscales of the AQ, social skills and communication, parents of people with autism obtained higher scores than control parents. The other three scales, attention to detail, attention switching, and imagination, did not differentiate groups. The correlation between social skills and communication scales was .663. The scales can be combined to give an index of broad phenotype.The AQ appears to be sensitive to the broad phenotype, provided attention is restricted to the social skills and communication scales.

Abstract

Most developmental disorders are defined by an achievement discrepancy in which achievement on one or more specific abilities is substantially less than a person's measured intelligence. We evaluated the validity of this discrepancy criterion by assessing parameters that determine variability across abilities and by assessing relationships between achievement discrepancies and behavioral disturbances.Measures of intelligence, language, motor coordination, empathic ability, and attentional control were administered to a representative sample of 390 children aged 3 to 12 years. Parent ratings of child behavior were obtained.Results indicate that achievement discrepancies are a function of the correlation between ability measures, the shape of the ability distributions, and position on an index ability dimension. Discrepancies in achievement were not related to behavioral disturbance, but underachievement relative to age peers was invariably related to behavioral disturbance.We conclude that developmental disorders need to be redefined in ways that are consistent with how Mental Retardation is now defined, by (a) underachievements, (b) of defined magnitude, (c) using standardized measures, (d) with known relations to normal development, and (e) concurrent deficits on standardized measures of impaired function.

Abstract

Two tests of phonological processing, nonword repetition, and nonsense passage reading, were administered to 80 probands with autistic disorder or PDDNOS (index cases) and 59 typically developing controls, together with their parents and siblings. In addition, parents completed a questionnaire about history of language and literacy problems, and all participants were given tests of verbal (VIQ) and performance IQ (PIQ). Parents also completed the Autism-Spectrum Quotient, which was used to index the broad autism phenotype. Index probands scored well below control probands on the two phonological tests. However, on neither phonological measure did index relatives differ from control relatives. Within the index group, there was no relationship between the proband's level of VIQ, or age at achieving phrase speech, and phonological score of relatives. VIQ was the only measure to show any familiality within the index group. Reported history of language and literacy problems did not differentiate index parents from control parents overall, but those who were categorized as cases of the broad phenotype reported more history of language and literacy problems than did other index parents. However, they did not have poorer scores on the phonological measures. It is concluded that phonological processing deficits are not part of the broad autism phenotype.

Abstract

Autism is considered to have a genetic basis, although exposure to certain stimuli in the prenatal period has been implicated to be causal in some cases. Some investigations have shown an association with obstetric complications but findings have been inconsistent owing to differences in sampling and methods.To examine the association of obstetric factors with autism spectrum disorders for a cohort of children, using obstetric data contained in a statutory database collected at the time of birth.Subjects born in Western Australia between 1980 and 1995 and diagnosed with an autism spectrum disorder by 1999 were included as cases (n = 465). Siblings of the cases (n = 481) and a random population-based control group (n = 1313) were compared with the cases on obstetric information contained in the Maternal and Child Health Research Database of Western Australia.Compared with control subjects, cases had significantly older parents and were more likely to be firstborn. Case mothers had greater frequencies of threatened abortion, epidural caudal anesthesia use, labor induction, and a labor duration of less than 1 hour. Cases were more likely to have experienced fetal distress, been delivered by an elective or emergency cesarean section, and had an Apgar score of less than 6 at 1 minute. Cases with a diagnosis of autism had more complications than those with pervasive developmental disorder not otherwise specified or Asperger syndrome. Nonaffected siblings of cases were more similar to cases than control subjects in their profile of complications.Autism is unlikely to be caused by a single obstetric factor. The increased prevalence of obstetric complications among autism cases is most likely due to the underlying genetic factors or an interaction of these factors with the environment.

Abstract

Deletions of the sub-telomeric region of chromosome 22 have been associated with mental retardation, developmental delay, and autistic behaviors. This study investigated sub-telomeric anomalies of chromosome 22 using fluorescent in situ hybridization (FISH) probes in 82 subjects diagnosed with autism and atypical autism. No microdeletions were detected in this group. Similar FISH analyses were undertaken on two children with developmental delay, who were ascertained to be ring 22 during routine cytogenetic investigations. One subject was shown to have a microdeletion in the sub-telomeric region tested. Both children met the social and communication cut off for autism on the ADI and but did not meet the cut off for restrictive and repetitive behaviors. Only one of the two children met the criteria for PDD on the ADOS.

Abstract

Tumor necrosis factor alpha (TNFalpha), a cytokine involved in inflammatory processes, has been implicated in the pathophysiology of schizophrenia. The chromosomal location in the major histocompatibility complex (MHC) region on 6p21.1-21.3, a region with evidence for linkage, suggests a role in susceptibility to schizophrenia. Association of the minor (A) allele of the -G308A TNFalpha gene polymorphism with schizophrenia has been reported [Mol. Psychiatry 6 (2001) 79].Association of the -G308A TNFalpha gene and the lymphotoxin alpha (LTalpha)+A252G gene polymorphisms with schizophrenia was studied in 79 sib pair families with linkage in the MHC region and in 128 trio families using the transmission disequilibrium test (TDT).Weak association of the common G allele was detected for TNFalpha -G308A in both samples independently with borderline significance in the sib pair families (0.064) and with a nominally significant value of P=0.022 in the trio families. Combining both samples produced P=0.003, while LTalpha+A252G, located approximately 2-3 kb distally, revealed P=0.03 and the two locus haplotype yielded a P value of 0.001.Our data suggests association of the common G allele of the -G308A TNFalpha gene polymorphism with schizophrenia in a sample of 207 families. However, linkage disequilibrium with a different allele of the TNFalpha gene or another gene in the MHC region cannot be excluded.

Abstract

Previous studies have found that rates of suicide have a distinct annual rhythm with a peak in spring. Two recent European studies, however, have found that the amplitude of this rhythm has decreased over time. The purpose of this study was to examine whether such effects are found in Australia. Australian Bureau of Statistics data on all suicides in Australia 1970-1999 were analysed by spectral analysis. We found that suicide, violent suicide and suicide by males are seasonal and that the seasonal amplitude has increased over time. Males who use violent methods determine the seasonal effect. These results support previous findings that suicide and particularly violent suicide have a characteristic seasonal rhythm. However, the progressive increase in the amplitude of this rhythm over time in Australia is in direct contrast to other European findings. We suggest that this may be related to differences in patterns of anti-depressant use and also the effect of migration on the number of seasonally vulnerable individuals in Australia.

Abstract

The objective of this analysis is to explore the possibility that Brearley's failure to detect a coherent pattern of seasonal variation in his well-known study of homicide in the United States was due to a lack of statistical refinement. The original data on homicides in the United States between 1923 and 1928 (N = 51,798) were reanalyzed using spectral analysis. The results show a significant seasonal dependency with a peak in the homicide rate in August. The seasonal dependency explains between 23% and 30% of the total homicide variance. The importance of this finding is the degree of explained variance and the location of the peak, which is remarkably consistent with more contemporary studies using similar methods despite substantial sociodemographic changes, suggesting an endogenous etiology.

Abstract

As schizophrenia is genetically and clinically heterogeneous, systematic investigations are required to determine whether ICD-10 or DSM-IV categorical diagnoses identify a phenotype suitable and sufficient for genetic research, or whether correlated phenotypes incorporating neurocognitive performance and personality traits provide a phenotypic characterisation that accounts better for the underlying variation. We utilised a grade of membership (GoM) model (a mathematical typology developed for studies of complex biological systems) to integrate multiple cognitive and personality measurements into a limited number of composite graded traits (latent pure types) in a sample of 61 nuclear families comprising 80 subjects with ICD-10/DSM-IV schizophrenia or schizophrenia spectrum disorders and 138 nonpsychotic first-degree relatives. GoM probability scores, computed for all subjects, allowed individuals to be partly assigned to more than one pure type. Two distinct and contrasting neurocognitive phenotypes, one familial, associated with paranoid schizophrenia, and one sporadic, associated with nonparanoid schizophrenia, accounted for 74% of the affected subjects. Combining clinical diagnosis with GoM scores to stratify the entire sample into liability classes, and using variance component analysis (SOLAR), in addition to parametric and nonparametric multipoint linkage analysis, we explored candidate regions on chromosomes 6, 10 and 22. The results indicated suggestive linkage for the familial neurocognitive phenotype (multipoint MLS 2.6 under a low-penetrance model and MLS>3.0 under a high-penetrance model) to a 14 cM area on chromosome 6, including the entire HLA region. Results for chromosomes 10 and 22 were negative. The findings suggest that the familial neurocognitive phenotype may be a pleiotropic expression of genes underlying the susceptibility to paranoid schizophrenia. We conclude that use of composite neurocognitive and personality trait measurements as correlated phenotypes supplementing clinical diagnosis can help stratify the liability to schizophrenia across all members of families prior to linkage, allow the search for susceptibility genes to focus selectively on subsets of families at high genetic risk, and augment considerably the power of genetic analysis.

Abstract

Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be associated with schizophrenia (Straub et al. 2002a). There is no doubt that replication in other independent samples would enhance the significance of this finding considerably. Since the gene is located in the center of the linkage peak on chromosome 6p that we reported earlier, we decided to test six of the most positive DNA polymorphisms in a sib-pair sample and in an independently ascertained sample of triads comprising 203 families, including the families for which we detected linkage on chromosome 6p. Evidence for association was observed in the two samples separately as well as in the combined sample (P=.00068 for SNP rs760761). Multilocus haplotype analysis increased the significance further to .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype. Estimation of frequencies for six-locus haplotypes revealed one common haplotype with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted, parental haplotypes. All other six-locus haplotypes occurring at a frequency of >1% were less often transmitted than nontransmitted. Our results represent a first successful replication of linkage disequilibrium in psychiatric genetics detected in a region with previous evidence of linkage and will encourage the search for causes of schizophrenia by the genetic approach.

Abstract

Autism is considered by many to be the most strongly genetically influenced multifactorial childhood psychiatric disorder. In the absence of any known gene or genes, the main support for this is derived from family and twin studies. Two recent studies (Greenberg et al. 2001; Betancur et al. 2002) suggested that the twinning process itself is an important risk factor in the development of autism. If true, this would have major consequences for the interpretation of twin studies. Both studies compared the number of affected twin pairs among affected sib pairs to expected values in two separate samples of multiplex families and reported a substantial and significant excess of twin pairs. Using data from our epidemiological study in Western Australia, we investigated the possibility of an increased rate of autism in twins. All children born between 1980 and 1995 with autism, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) were ascertained. Of the 465 children with a diagnosis, 14 were twin births (rate 30.0/1,000) compared to 9,640 children of multiple births out of a total of 386,637 births in Western Australia between 1980 and 1995 (twin rate weighted to number of children with autism or PDD per year 26.3/1,000). These data clearly do not support twinning as a substantial risk factor in the etiology of autism. We demonstrate that the high proportion of twins found in affected-sib-pair studies can be adequately explained by the high ratio of concordance rates in monozygotic (MZ) twins versus siblings and the distribution of family size in the population studied. Our results are in agreement with those of two similar studies by Croen et al. (2002) in California and Hultman et al. (2002) in Sweden.

Abstract

The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31.

Abstract

To describe three Gypsy families with Marinesco-Sjögren syndrome (MSS), demyelinating neuropathy, and recurrent episodes of myoglobinuria in five of the six affected subjects. Because these families originated from the same genetically isolated founder population as did patients with congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, and because the two syndromes have clinical manifestations in common, we hypothesized that the two related, albeit distinct, syndromes may represent clinical variants of a single genetic disorder.Clinical studies were conducted and linkage and haplotype analyses were performed for the three families. A total of 16 individuals, including the 6 with MSS and 10 unaffected relatives, were genotyped for six polymorphic microsatellite markers from the CCFDN region on 18qter.Linkage analysis of markers in the 18qter region, where we previously had located the CCFDN gene, produced a lod score of 3.55, demonstrating colocalization of the gene responsible for MSS with demyelinating neuropathy and myoglobinuria with the CCFDN gene. Moreover, the patients with MSS shared the conserved marker haplotype found in CCFDN chromosomes.These data suggest that Marinesco-Sjögren syndrome with peripheral neuropathy and myoglobinuria, and congenital cataracts facial dysmorphism neuropathy syndrome are genetically identical and are caused by a single founder mutation.

Abstract

The accurate clinical diagnosis of Alzheimer's disease can only be made with a high degree of certainty in specialized centres. The identification of predictive or diagnostic genetic factors may improve accuracy of disease prediction or diagnosis. One major genetic risk factor, the epsilon4 allele of the apolipoprotein E gene, is universally recognised. We have recently shown that the A allele of the apolipoprotein E, -491A/T promoter polymorphism is also an important risk factor for Alzheimer's disease in an Australian population. We designed the present study to investigate the association between apolipoprotein E genotype, -491A/T polymorphism, plasma apoE levels and the subjective experience of memory decline among 98 subjects and 49 age, gender and education-matched normal controls. An increased frequency of the epsilon4 allele of apolipoprotein E was significantly associated with the 'memory complainers' group (OR = 2.35, P = 0.02) as was the A allele of the -491A/T polymorphism (OR = 2, P = 0.02). Among all subjects, only seven individuals were homozygous for both of these alleles, and six of these seven individuals belonged to the 'memory complainers' group. This sub-group also had relatively elevated plasma apolipoprotein E levels (P < 0.01) and tended to score lower on the Mini-Mental State Examination (MMSE) and Cambridge Cognition Test. These data suggest that the epsilon4 allele of apolipoprotein E and the -491A allele are over-represented among individuals who complain of memory difficulties. Follow-up studies should clarify whether these genotypes and phenotypes are useful in the prediction and/or diagnosis of Alzheimer's disease.

Abstract

Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of early-onset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-epsilon4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P < 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.

Abstract

Advances in genetic analysis as well as progress in the Human Genome Sequencing Project have raised the hope to elucidate the molecular basis of mental disorders on the DNA level. In the present review we describe and discuss the basic concepts which are currently applied for the genetic approach in order to find DNA variations associated with a disorder. A prerequisite for such studies is the confirmed evidence for genetic transmission established by family-, twin-, and adoption studies. We describe the study design and discuss the mode of inheritance for complex genetic traits in comparison to monogenic, Mendelian traits. Recombination as a basis for linkage analysis is explained and its implication for classical LOD score analysis in families, as well as for affected sib-pair analysis and for analysis of linkage disequilibrium is discussed. Moreover, we describe types of markers and maps used in these studies. We explain and discuss the association approach in conjunction with the Human Genome Project. Finally, we stress possible implications for diagnosis, prevention and new therapeutic approaches.

Abstract

Previous studies concerning Alu I/D polymorphism in the ACE gene and ADPKD severity have used the Alu genotypes as a representative of the true biological variable, namely ACE activity. However, wide individual and ethnic differences in the proportion of variance in ACE activity explained by the I/D genotype may have confounded these studies. This investigation examines the association between ADPKD severity and ACE in terms of plasma enzyme activity and I/D genotypes in individuals from three different countries.Blood samples were collected from 307 ADPKD patients (116 Australian, 124 Bulgarian and 67 Polish) for determination of ACE activity levels and I/D genotypes. Chronic renal failure (CRF) was present in 117 patients and end-stage renal failure (ESRF) in 68 patients.ACE activity was related to the I/D genotype, showing a dosage effect of the D allele (P=0.006). The proportion of variance due to the Alu polymorphism was 14%. No difference in ACE activity and I/D genotype distribution was found between patients with CRF versus normal renal function (P=0.494; P=0.576) or between those with ESRF versus those without ESRF (P=0.872; P=0.825). No effect of the I/D genotype on age at development and progression to renal failure (CRF; ESRF) was detected in the overall group, and in subgroups based on ethnic origin, linkage status and sex.ACE is not likely to play a role as a determinant of ADPKD phenotype severity.

Abstract

A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.

The epidemiology of the genetic liability for schizophreniaAUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRYHallmayer, J.2000; 34: S47-S55

Abstract

The low incidence of schizophrenia prohibits large scale prevention trials, and the question arises whether such studies become more feasible by taking into account genetic factors. The aim of the paper was to inform preventive endeavours with an account of the genetic background to schizophrenia.The family, twin and adoptive studies of schizophrenia are reviewed and recent molecular genetic data presented.Children of a parent diagnosed with schizophrenia have a ten-fold increased risk of developing the disorder. Twin and adoption studies strongly suggest the risk increase is mainly due to genetic factors. On an individual level, a positive family history is the strongest known risk factor for schizophrenia. For a prevention study, very large numbers of families have to be screened in order to reach a sufficient sample size.One obvious way to increase the accuracy of predicting who is at high risk of developing schizophrenia would be to find specific mutations in the human genome. Attempts to isolate specific genes by means of linkage and association studies have been unsuccessful so far and, given the number of genes involved, it is extremely unlikely that the predictive value of individual genes will be high enough to warrant intervention. Genetic studies also suggest the genetic liability extends beyond the traditional clinical phenotypes. Prevention trials might become possible by adopting a broader approach.

Abstract

Evidence from epidemiological studies and segregation analysis suggests oligo- or polygenic inheritance in schizophrenia. Since model independent methods are thought to be most appropriate for linkage analysis in complex disorders, we performed a genome-wide autosomal screen in 71 families from Germany and Israel containing 86 independent affected sib-pairs with parental genotype information for statistical analysis strictly identity by descent. We genotyped 305 individuals with 463 markers at an average distance of approximately 10 cM genome-wide, and 1-2 cM in candidate regions (5q, 6p, q, 8p, 10p, 18p, 22q). The highest multipoint LOD scores (ASPEX) were obtained on 6p (D6S260, LOD = 2.0; D6S274, LOD = 2.2, MHC region, LOD = 2.15) and on 10p (D10S1714, LOD = 2.1), followed by 5q (D5S2066, LOD = 1.36), 6q (D6S271, LOD = 1.12; D6S1613, LOD = 1.11), 1q (D1S2675, LOD = 1.04), and 18p (broad disease model: D18S1116, LOD = 1.0). One hundred and thirty-three additional family members were available for some of the families (extended families) and were genotyped for these regions. GENEHUNTER produced a maximum NPL of 3.3 (P = 0.001) for the MHC region and NPL of 3.13 (P = 0.0015) for the region on 10p. There is support for these regions by independent groups. In genome-wide TDT analysis (sTDT, implemented in ASPEX), no marker passed the significance level of 0.0001 given by multiple testing, but nominal significance values for D10S211 (P = 0.03) and for GOLF (P = 0.0032) support further the linkage results on 10p and 18p. Our survey of 22 chromosomes identified candidate regions which should be useful to screen for schizophrenia susceptibility genes.

Abstract

This study was performed to establish the incidence of catatonia in a psychiatric intensive care unit, to test the Bush-Francis Catatonia Screening Instrument (BFCSI) and to assess the response of catatonic signs to benzodiazepines. During a 12-month period all patients admitted to a psychiatric intensive care unit were screened for catatonic signs using the BFCSI. Patients with catatonia were further assessed with the Bush-Francis Catatonia Rating Scale (BFCRS), the Modified Rogers Scale (MRS), and scales for associated psychotic and parkinsonian symptoms. They were treated with oral lorazepam or parenteral clonazepam and their responses evaluated daily. Neuroleptics were stopped for at least 3 days. Twenty four patients met the DSM IV criteria for catatonia, giving an incidence of 15% with a significantly higher proportion of non-Europeans. The most common associated diagnosis was schizophrenia (54%). Twenty two patients completed the benzodiazepine trial. All showed significant responses after 3 days of treatment. Sixteen (16/22, 73%) had full remission within 6 days, most within 2 to 4 days. Partial responders (n = 6) all had schizophrenia and were more likely to have longer pre-trial catatonic episodes. We find the BFCSI a simple and reliable tool to screen for catatonia, and our data attest to the efficacy of benzodiazepines in the treatment of catatonia.

Abstract

The deposition of beta amyloid is a critical event in the pathogenesis of Alzheimer's disease. This peptide is a metabolite of the amyloid precursor protein. Recent research suggests that there is a correlation between plasma insulin and glucose concentrations and memory performance in Alzheimer's disease sufferers. Additionally, in vitro evidence suggests that both insulin and glucose may affect the metabolism of amyloid precursor protein and therefore the production of beta amyloid--however, to our knowledge no in vivo data have yet been published. We investigated the effect of elevated plasma levels of glucose and insulin on the plasma concentration of amyloid precursor protein in non-Alzheimer's disease subjects. As would be expected following ingestion of a glucose drink, blood insulin and glucose levels significantly increased. Interestingly, however, plasma amyloid precursor protein concentration decreased. Whilst no correlation was observed between insulin or glucose levels and plasma amyloid precursor protein concentration, the decrease in plasma amyloid precursor protein concentration was affected by the apolipoprotein E genotype of the subject. Possession of an epsilon4 allele resulted in a reduced decrease in plasma amyloid precursor protein in response to glucose ingestion when compared to non-epsilon4 subjects. We conclude that glucose ingestion, and the subsequent elevation of plasma levels of glucose and insulin leads to a decrease in plasma amyloid precursor protein concentration. Further studies are required to determine the clinical significance of these physiological changes in plasma amyloid precursor protein and the implications for Alzheimer's disease pathogenesis.

Abstract

Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20-50 years. Newborn screening data suggest that the gene frequency is very low worldwide but is higher among the Roma in Europe. Since the cloning of the galactokinase gene (GK1) in 1995, only two disease-causing mutations, both confined to single families, have been identified. Here we present the results of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass screening. Genetic linkage mapping placed the disease locus on 17q, and haplotype analysis revealed a small conserved region of homozygosity. Using radiation hybrid mapping, we have shown that GK1 is located in this region. The founder Romani mutation identified in this study is a single nucleotide substitution in GK1 resulting in the replacement of the conserved proline residue at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is approximately 5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.

Abstract

Chromosomal region 15q11-q13 has been implicated to harbor a susceptibility gene or genes underlying autism. Evidence has been derived from the existence of cytogenetic anomalies in this region associated with autism, and the report of linkage in a modest collection of multiplex families. Most recently, linkage disequilibrium with the marker GABRB3-155CA2 in the candidate locus GABRB3, located in this region, has been reported. We searched for linkage using eight microsatellite markers located in this region of chromosome 15 in 147 affected sib-pairs from 139 multiplex autism families. We also tested for linkage disequilibrium in the same set of families with the same markers. We found no evidence for excess allele sharing (linkage) for the markers in this region. Also, we found no evidence of linkage disequilibrium, including for the locus GABRB3-155CA2. Thus, it appears that the role of this region of chromosome 15 is minor, at best, in the majority of individuals with autism.

Abstract

We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying =10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary.

Abstract

To determine the molecular basis for autosomal dominant intermediate hereditary motor and sensory neuropathy (HMSN) in a four generation family. The gene defects in families with intermediate HMSN are not known, but it has been suggested that most have X linked HMSN.All participating family members were examined clinically. Genomic DNA was obtained from 10 affected and seven unaffected members. Linkage analysis for the known HMSN loci was first performed. Mutations in the peripheral myelin protein zero gene (PMP0) were sought in two affected members, using one unaffected member for comparison, by amplification of the six exons of the gene followed by single strand conformation polymorphism (SSCP) analysis, dideoxy fingerprinting (ddF), and sequencing. Subsequently, the mutation was screened for in all affected and unaffected members in the family using Alu I digestion and in 100 unrelated control subjects using "snap back" SSCP analysis. Sequencing of cDNA from a sural nerve biopsy from an affected member was also performed.The clinical phenotype was of variable severity, with motor nerve conduction velocities in the intermediate range. Linkage to PMP0 was demonstrated. Analysis of genomic DNA and cDNA for PMP0 identified a novel codon 35 GAC to TAC mutation. The mutation produces an inferred amino acid change of aspartate to tyrosine at codon six of the processed protein (Asp6Tyr) in the extracellular domain and was present in all affected family members but not in 100 unrelated controls.The present findings further extend the range of phenotypes associated with PMP0 mutations and indicate that families with "intermediate" HMSN need not necessarily be X-linked as previously suggested.

Abstract

The aim of this paper is to determine the efficacy of dexamphetamine in adult attention deficit hyperactivity disorder (ADHD) in a naturalistic setting.A randomised, double-blind, placebo-controlled study of dexamphetamine was conducted by two psychiatrists in private practice who saw a total of 68 consecutive referrals of patients thought to have ADHD by their referring general practitioners. Patients were admitted to the study if their current level of ADHD symptoms satisfied DSM-IV criteria (modified for use in adults), and were not currently comorbid for major mood disturbance or substance abuse. Response to medication was assessed by repeated administration of these modified DSM-IV criteria, self- and relatives' rating, as well as clinician rating using the Clinical Global Impressions Scale. More general outcome measures included the Brief Symptom Inventory and a patient satisfaction questionnaire. Medication side effects were recorded, including monitoring blood pressure and weight change. Urinalysis monitored concurrent substance usage and compliance.Dexamphetamine had a significant therapeutic response exceeding the placebo response (p = 0.045). The response was similar in both genders and across the age range. It was detected by patients, their relatives and the two clinicians. The only significant side effect was weight loss. One patient on dexamphetamine discontinued the trial because of an event possibly related to the medication.In the short term, dexamphetamine appears to be efficacious in treating adult ADHD. As this is the first study in the literature, the result requires replication. Given that stimulant medication use in adult ADHD appears to be long-term, studies of long-term efficacy need to be carried out.

Abstract

The chromosome 22 workshop took place at the Sixth World Congress on Psychiatric Genetics from October 6th-10th, 1998 in Bonn, Germany. Aim of the workshop was to summarize the findings in psychiatric genetics on chromosome 22. Four reports concerning a susceptibility locus for schizophrenia and one report on bipolar disorder were given. A potential locus for nocturnal enuresis has been suggested to reside on chromosome 22.

Abstract

Several studies have suggested a role for the histocompatibility complex of loci (HLA) in the genetic susceptibility to autism. We have tested this hypothesis by linkage analysis using genetic marker loci in the HLA region on chromosome 6p in multiplex families with autism. We have examined sharing of alleles identical by descent in 97 affected sib pairs from 90 families. Results demonstrate no deviation from the null expectation of 50% sharing of alleles in this region; in fact, for most marker loci, the observed sharing was less than 50%. Thus, it is unlikely that loci in this region contribute to the genetic etiology of autism to any significant extent in our families.

Abstract

A possible association between the small conductance calcium-regulated potassium channel gene, hSKCa3, and schizophrenia has recently been described by Chandy et al using a case-control design with patients with schizophrenia (n=141) and matched controls (n = 158). The gene may be considered as an excellent candidate gene for psychiatric disorders, since it plays a role in modulating neuronal firing patterns by regulating the slow component of after hyperpolarisation. In addition, the gene contains a highly polymorphic trinucleotide sequence (CAG) within exon 1, which encodes a polyglutamine stretch. The possible contribution of unstable trinucleotide repeats to the development of psychiatric disorders has previously been discussed. Chandy et al reported an over-representation of alleles with higher repeat number in schizophrenics as compared to controls (P = 0.0035). In an attempt to replicate these findings, we have performed a family-based study with 193 offspring/parent combinations using a sample of 49 multiplex families (two or more affected siblings with parents) and a second sample of 83 simplex families (one affected offspring with parents). No evidence for the association of longer repeats with schizophrenia was obtained when each sample was tested separately or when both samples were combined and tested for transmission disequilibrium.

Abstract

Recent evidence suggests that a polymorphism in the regulatory region of the apolipoprotein E gene (APOE) is associated with an increased risk for developing Alzheimer's disease (AD) independent of that conveyed by the epsilon4 allele of APOE. Previous work by our group indicated that plasma apolipoprotein E (apoE) levels were elevated in AD, raising the possibility that the -491 genotype might modify AD risk by increasing expression of the APOE gene. In a total of 638 individuals the -491AA genotype was significantly associated with AD (P < 0.005) while the TT genotype was associated with controls (P < 0.005). In 138 individuals the AA genotype showed significantly higher plasma apoE levels, independent of epsilon4 and AD status (P < 0.01) as well as within control and AD groups (P < 0.05). Within the AD group the AA genotype showed increased apoE levels when compared to AA controls (P < 0.0001). These results suggest that the -491 AA genotype is associated with increased plasma apoE levels, providing a potential basis for elucidating how that genotype increases the risk for developing AD.

Abstract

The distal myopathies are clinically, pathologically and genetically heterogenous. Thus far, seven types of distal myopathy have been linked to four chromosome loci. We recently examined four affected members from three generations of an autosomal dominant distal myopathy kindred. A muscle biopsy was performed on the index case. Muscle histopathology showed non-specific myopathic findings including increased variation in fiber size and increased internalized nuclei. No abnormal inclusions or vacuoles were present. Microsatellite markers for the four distal myopathy loci on chromosomes 2, 9 and 14 were studied on affected and several unaffected family members. Affected patients developed distal weakness in anterior foreleg muscles followed by progressive distal upper and proximal lower extremity involvement. Chromosome 2, 9 and 14 regional markers were informative and demonstrated recombinations with affected individuals in the pedigree. The resulting LOD scores obtained from the multipoint analyses gave no evidence of positive linkage to any of the regions and positively excluded (LOD score less than -2) all, or virtually all, of the candidate regions examined. This autosomal dominant distal myopathy family does not show evidence of linkage to any of the known distal myopathy loci, suggesting the existence of at least one more distal myopathy locus. Furthermore, the clinical and pathological features appear distinct from other previously described but genetically-undetermined autosomal dominant distal myopathies.

Abstract

The present study tests the hypothesis that the 9-repeat allele of the dopamine transporter gene (DAT1; SLC6A3) is more frequent in alcohol-dependent probands--and in particular those with severe withdrawal symptoms (seizures and/or delirium)--compared to nonalcoholics.To avoid stratification effects, the family-based association approach of Falk and Rubinstein was used in our sample of 87 alcohol-dependent probands and their biological parents.By applying a family-based association approach, we were not able to detect significant association between allele 9 at DAT1 (SLC6A3) and alcoholism as well as between patients with or without severe withdrawal symptoms.Based on our data, the impact of the 9-repeat allele of the dopamine transporter gene in alcoholism and the severity of alcohol withdrawal symptoms is putatively not substantial.

Abstract

The epsilon4 allele of apolipoprotein E gene is a major risk factor for Alzheimer's disease. However, the mechanism by which the E4 isoform of apolipoprotein E increases the risk of Alzheimer's disease is poorly understood. To determine whether the isoform-specific effects of apolipoprotein E may be mediated via clearance of bound beta-amyloid, we examined the uptake of beta-amyloid 1-40 into Chinese hamster ovary cells in the presence or absence of the apolipoprotein E isoforms E2, E3 and E4. Apolipoprotein E2 and E3 treatments were associated with higher association of beta-amyloid with cells as compared to treatment with E4. Heparin blocked the association of beta-amyloid with cells, as did an antibody to one of the apolipoprotein E receptors (the low-density lipoprotein receptor-related protein). Thus, the apolipoproteins E2 and E3, but not E4, may play important roles in the clearance of beta-amyloid from the extracellular space via the low-density lipoprotein receptor-related protein.

Abstract

The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic CA-repeat marker G-olfalpha on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely spaced around G-olfalpha yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olfalpha. Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olfalpha was transmitted 47 times and was not transmitted 21 times (P=.009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.

Abstract

The existence of a psoriasis susceptibility locus, PSORS1 (HUGO/GDB-approved symbol), in or near the HLA region of chromosome 6 is strongly supported by a lod score analysis of HLA-B and psoriasis in 97 families from 16 published datasets. Families included in the dataset represent all the psoriasis families with usable HLA data that we could find in the published literature through May 1997. The recombination fraction between PSORS1 and HLA-B is estimated to be at or near 0.00, with a maximum two-point lod score of 23.7, assuming a dominant mode of inheritance with low (20%) penetrance at the PSORS1 locus. Although these families are geographically and ethnically diverse, there is no evidence for linkage heterogeneity at the HLA-linked locus in this analysis. We also conclude that the HLA-B17 allele, which is strongly associated with psoriasis, is unlikely itself to contribute directly to psoriasis susceptibility; rather, the HLA-B locus is probably tightly linked to the PSORS1 locus. Finally, we raise the possibility of a two-locus/heterogeneity model as one way to reconcile several findings in the literature.

Abstract

We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene. PS-1 intronic allele 1 homozygosity was not associated with individuals with early- or late-onset sporadic Alzheimer's disease (EOAD or LOAD). Carriers for the PS-1 intronic allele 1 were also not associated with significantly increased risk for AD regardless of gender. Our results for the Australian population are consistent with those of recent reports for other populations and do not support the conclusion that the PS-1 intronic polymorphism is associated with AD.

Abstract

DQCAR is a (CA)n microsatellite located in the HLA class II region and tightly linked to HLA-DQB1. Previous studies showed a strikingly low level of size variation in DQCAR alleles within an extensive subfamily of HLA-DQ subtypes (DQ1). DQCAR alleles in non-DQ1 subtypes showed a higher degree of size polymorphism. In this study sequence analysis demonstrates that DQ1-associated DQCAR alleles have a single C-->A nucleotide substitution interrupting the CA repeat array. Frequent CA-->GA mutations are also observed in DQ1-associated microsatellites with identical allele sizes. In contrast, DQCAR alleles associated with non-DQ1 haplotypes display a perfect CA repeat sequence and the variation in allele size is attributable only to differences in the number of CA repeats. Our results imply that several mutational mechanisms are involved in the generation of allelic diversity within the same microsatellite locus. The possibility of different mutation rates in the same locus should to be taken into account when using these markers in evolutionary and disease studies.

Abstract

Suggestive evidence for a potential susceptibility locus for schizophrenia at 5q31 was obtained in two family samples. Sample I consisted of 14 families with schizophrenia and revealed for the marker IL9 a lod score of 1.8 by two point lod score analysis. Sample II comprised 44 families including four from sample I and was ascertained in order to employ affected sib-pair analysis by identity by descent. A lod score of 1.8 around the marker D5S399 was obtained by multipoint analysis. The lod score remained positive, but decreased to 1.27 when the four families from sample I were excluded in order to use sample II as a statistically independent replication sample. We propose a susceptibility locus for schizophrenia with probably minor contribution in the pedigrees under investigation.

Mutation rate varies among alleles at a microsatellite locus: Phylogenetic evidencePROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAJin, L., Macaubas, C., Hallmayer, J., Kimura, A., Mignot, E.1996; 93 (26): 15285-15288

Abstract

The understanding of the mutational mechanism that generates high levels of variation at microsatellite loci lags far behind the application of these genetic markers. A phylogenetic approach was developed to study the pattern and rate of mutations at a dinucleotide microsatellite locus tightly linked to HLA-DQB1 (DQCAR). A random Japanese population (n = 129) and a collection of multiethnic samples (n = 941) were typed at the DQB1 and DQCAR loci. The phylogeny of DQB1 alleles was then reconstructed and DQCAR alleles were superimposed onto the phylogeny. This approach allowed us to group DQCAR alleles that share a common ancestor. The results indicated that the DQCAR mutation rate varies drastically among alleles within this single microsatellite locus. Some DQCAR alleles never mutated during a long period of evolutionary time. Sequencing of representative DQCAR alleles showed that these alleles lost their ability to mutate because of nucleotide substitutions that shorten the length of uninterrupted CA repeat arrays; in contrast, all mutating alleles had relatively longer perfect CA repeat sequences.

Abstract

Genetic factors undoubtedly play a major etiologic role in autism, but how it is inherited remains unanswered. The increased incidence in males suggests possible involvement of the X chromosome.Using data from 38 multiplex families with autism (2 or more autistic siblings), we performed a multipoint sib-pair linkage analysis between autism and 35 microsatellite markers located on the X chromosome. The model included a single parameter, the risk ratio lambda xs (i.e., ratio of risk to siblings compared with the population prevalence), owing to an X-linked gene. Different lambda xs values were assumed and regions of exclusion were established.The entire X chromosome could be excluded for a lambda xs value of 4. The ability to exclude an X-linked gene decreased with smaller lambda xs values, and some positive evidence was obtained with smaller values. A maximum lod score of 1.24 was obtained at locus DXS424 with a lambda xs value of 1.5.We were able to exclude any moderate to strong gene effect causing autism on the X chromosome. Smaller gene effects (lambda xs < 4) could not be excluded, in particular, a gene of small effect located between DXS453 and DXS1001.

Abstract

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

Abstract

This study explores the genetic relationship between schizophrenia and the dopamine transporter gene (DAT) by a variety of methods. In a sample of 48 families--each family containing at least one nuclear family with a pair of affected siblings--we performed linkage analysis using the maximum likelihood (LOD score) method as well as sibpair analysis (identity by descent). In addition, we investigated a sample of 108 nuclear families--index case affected with schizophrenia/chronic schizoaffective disorder--for association using the haplotype relative risk method. Linkage between schizophrenia and DAT using two- and three-point linkage analysis was excluded with all disease models employed. No evidence for association between haplotypes of the VNTR-probe of the DAT and schizophrenia has been detected. Thus, a contribution of the DAT gene to the genetic diathesis of schizophrenia is unlikely in the families studied.

Abstract

Despite strong genetic influences in autism, the true mode of inheritance remains unknown. Sex differences in autism have been described in both singleton and multiplex families [Lord et al., 1982; Volkmar et al., 1993; McLennan et al., 1993; Lord, 1992]: Boys outnumber girls by 3 or 4 to 1, and so a sex-linked mode of transmission must also be considered. The key characteristic of X-linkage is that all sons of affected men are unaffected (no male-to-male transmission). In the present study, which is part of an ongoing linkage project in autism, we describe 77 multiplex autism families, 11 of who are affected cousin or half-sibling families. By using these families, it is possible to trace the path of genetic transmission and observe whether the hypothesis of X-linkage is tenable. Of 11 extended pedigrees from 77 multiplex families, six show male-to-male transmission; in these families, X-linkage can be excluded as the genetic basis for their autism. The data from the other five families are compatible with either an autosomal or an X-linked mode of transmission. The key point to emerge, then, is that autism cannot be exclusively an X-linked disorder; there must be an autosomal mode of transmission at least in some families. Thus we must consider the alternative hypotheses that autism is either entirely autosomal, or it is genetically heterogeneous, involving at least one autosomal locus with genderspecific expression, as well as a possible locus on the X-chromosome.

Abstract

Replication was attempted of a recent report on linkage between bipolar affective disorder and pericentrometric loci on chromosome 18. Linkage to these markers was excluded in a sample of five extended multiplex families using lod-score and affected-pedigree-member methods. In one family, however, the lod score exceeded 1.0. Although the proposed susceptibility genes are unlikely to have a major impact on the occurrence of bipolar disorder, they might modify the genetic risk in a minority of familial cases.

Abstract

The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.

Abstract

In an attempt to replicate a potential linkage on chromosome 22q12-q13.1 reported by Pulver et al. [1994: Am J Med Genet 54:36-43], we have analyzed 4 microsatellite markers which span this chromosomal region, including the IL2RB locus, for linkage with schizophrenia in 30 families from Israel and Germany. Linkage analysis by pairwise lod score analysis as well as by multipoint analysis did not provide evidence for a single major gene locus. However, a lod score of Zmax = 0.612 was obtained for a dominant model of inheritance with the marker D22S304 at recombination fraction 0.2 by pairwise analysis. In addition, using a nonparametric method, sib pair analysis, a P value of 0.068 corresponding to a lod score of 0.48 was obtained for this marker. This finding, together with those of Pulver et al. [1994: Am J Med Genet 54:36-43] and Coon et al. [1994: Am J Med Genet 54:72-79], is suggestive of a genetic factor in this region, predisposing for schizophrenia in a subset of families. Further studies using nonparametric methods should be conducted in order to clarify this point.

Abstract

Linkage analysis was performed on 22 Bulgarian families with polycystic kidney disease (PKD) ascertained through the hemodialysis centers of two medical schools. A total of 128 affected and 59 unaffected individuals, and 54 spouses have been investigated using eight polymorphic markers linked to PKD1 and nine markers to PKD2. The results demonstrate locus heterogeneity with 0.67 as the maximum likelihood value of alpha, i.e., the proportion of families linked to PKD1. In five families, the results suggest linkage to PKD2 and observed recombinants place the gene between loci D4S1544 and D4S1542. In one family, two double recombinants for closely linked markers on chromosome 16 and on chromosome 4 give evidence for the lack of linkage to either PKD1 or PKD2, thus suggesting the involvement of a third locus. Analysis of clinical data in the PKD1 group versus the unlinked group shows no significant differences in the severity of the disease.

Abstract

A highly polymorphic (CA)n microsatellite marker (DQCAR), located between the DQA1 and the DQB1 genes, was characterized in four ethnic groups. Based on length polymorphism, 12 alleles could be defined. The marker is located 1- to 2-kb telomeric to the DQB1 gene and 10 kb centromeric to the DQA1 gene and was shown to be in tight linkage disequilibrium with HLA-DQ. Analysis of the linkage disequilibrium pattern revealed little additional diversity in DQ1-associated haplotypes. Almost all DQ1 subjects examined were DQCAR 103 or DQCAR 107 (13 and 15 CA repeats, respectively). In contrast, significant haplotypic diversity was observed for most DQ2-, DQ3-, and DQ4-associated haplotypes. These haplotypes often had longer allele sizes (DQCAR > 111, more than 17 CA repeats) and more DQCAR alleles per haplotype. These haplotypes also carried DQCAR alleles of different sizes, even though they bore the same DQA1 and DQB1 alleles, and sometimes the same DRB1 allele as well. These results indicate that DQCAR could be a useful marker to better define disease associations with HLA. Our results are also consistent with the hypothesis that CAR alleles with higher numbers of repeats have higher mutation rates and that recombination within the HLA-DR/DQ region is haplotype dependent.

Abstract

In the present study, we tested 19 Caucasian and 28 Black American narcoleptics for the presence of the human leucocyte antigen (HLA) DQB1*0602 and DQA1*0102 (DQ1) genes using a specific polymerase chain reaction (PCR)-oligotyping technique. A similar technique was also used to identify DRB1*1501 and DRB1*1503 (DR2). Results indicate that all but one Caucasian patient (previously identified) were DRB1*1501 (DR2) and DQB1*0602/DQA1*102 (DQ1) positive. In Black Americans, however, DRB1*1501 (DR2) was a poor marker for narcolepsy. Only 75% of patients were DR2 positive, most of them being DRB1*1503, but not DRB1*1501 positive. DQB1*0602 was found in all but one Black narcoleptic patient. The clinical and polygraphic results for this patient were typical, thus confirming the existence of a rare, but genuine form of DQB1*0602 negative narcolepsy. These results demonstrate that DQB1*0602/DQA1*0102 is the best marker for narcolepsy across all ethnic groups.

Abstract

Approximately 2%-5% of autistic children show cytogenetic evidence of the fragile X syndrome. This report tests whether infantile autism in multiplex autism families arises from an unusual manifestion of the fragile X syndrome. This could arise either by expansion of the (CGG)n trinucleotide repeat in FMR-1 or from a mutation elsewhere in the gene. We studied 35 families that met stringent criteria for multiplex autism. Amplification of the trinucleotide repeat and analysis of methylation status were performed in 79 autistic children and in 31 of their unaffected siblings, by Southern blot analysis. No examples of amplified repeats were seen in the autistic or control children or in their parents or grandparents. We next examined the hypothesis that there was a mutation elsewhere in the FMR-1 gene, by linkage analysis in 32 of these families. We tested four different dominant models and a recessive model. Linkage to FMR-1 could be excluded (lod score between -24 and -62) in all models by using probes DXS548, FRAXAC1, and FRAXAC2 and the CGG repeat itself. Tests for heterogeneity in this sample were negative, and the occurrence of positive lod scores in this data set could be attributed to chance. Analysis of the data by the affected-sib method also did not show evidence for linkage of any marker to autism. These results enable us to reject the hypothesis that multiplex autism arises from expansion of the (CGG)n trinucleotide repeat in FMR-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

The antipsychotic effects of dopamine D2 receptor antagonists (neuroleptics) and the psychotomimetic effects of dopamine agonists suggest that a defect of the D2 receptor gene might be a factor in the etiology of schizophrenia. Fifteen families that contained several members suffering from schizophrenia were tested for linkage between the D2 receptor gene and schizophrenia. In addition, four flanking markers were tested. The mode of inheritance was assumed to be dominant. Five different models of the affection status, which ranged from a narrow to a broad definition of the affection status, were studied. Linkage analysis was carried out with dominant, recessive, and intermediate modes of transmission. Two-point and multipoint analyses between schizophrenia and the D2 receptor gene resulted in log-likelihood differences < -2 for all five models, and linkage between this candidate gene and schizophrenia was excluded. A mutation in the D2 receptor gene itself is therefore extremely unlikely to be related to a higher susceptibility to schizophrenia, at least in the present group of families.

Abstract

The dopamine D4 receptor gene and the closely placed tyrosine hydroxylase (TH) receptor gene are important candidate genes for schizophrenia; both are located on the short arm of chromosome 11. Multipoint linkage analyses excluded linkage of schizophrenia/schizoaffective disorder to both candidate genes in a sample of 15 multiplex and systematically recruited families. This result was not dependent on the definition of the affection status and on the specification of the mode of transmission (insofar as it is monogenic) of the disease. There was no evidence for a subgroup of families being linked. This result does not preclude the possibility that the D4 receptor gene or the TH gene has only a nonmajor effect on the genetic etiology of schizophrenia or that families in other populations are linked.

Abstract

Evidence from twin and family studies strongly suggests that genetic factors play a prominent role in the etiology of some cases of infantile autism. Genetic factors would be expected to be especially strong in families with multiple autistic members (multiplex families). This report describes the identification and evaluation of 44 families with two or more autistic children collected as part of a genetic linkage study in autism. Families were referred with a presumptive classification of multiplex autism. Children referred as autistic, as well as their presumptively normal siblings, were assessed using the Autism Diagnostic Interview (ADI) and the Autism Diagnostic Observation Scale (ADOS). Thirty-seven of the 44 families (87%) had at least two children who met diagnostic criteria for autism on the ADI. Of the total group of 117 children evaluated in those families, 83 (71%) met all ADI criteria and could be unambiguously classified as autistic (affected), 26 (22%) met none of the ADI criteria and were classified as not autistic (unaffected), and 8 (7%) were classified as uncertain because they met one or more but not all of the ADI cutpoints. Autistic siblings were not significantly concordant for most autism characteristics, for IQ, or for verbal ability. Significant concordances were found, however, for behaviors related to rituals and repetitive play, and for social impairments in the expression and understanding of facial expressions of emotion.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

It is widely acknowledged that the genetic diatheses for schizophrenia and affective disorders are independent. However, there are increasing doubts about this classic view, and empirical evidence for a dichotomy of these two prototypes of functional psychoses is limited. A controlled family study of consecutive admissions was conducted to determine whether familial risks for schizophrenic (SCZ) and affective disorders were independent or overlapping.Index probands met Research Diagnostic Criteria for SCZ (n = 146), schizoaffective (SA [n = 115]), bipolar (BP [n = 80]), or unipolar major depressive (UP [n = 184]) disorder. Comparison probands met Research Diagnostic Criteria for alcoholism (n = 64) or were sampled from the general population (n = 109). A total of 2845 first-degree relatives were blindly diagnosed from interview, informant, and/or record data, with direct interviews completed in 2070 (82% of living first-degree relatives).By Cox's proportional hazards analysis, SCZ, SA, BP, and UP disorders were familial, in that each group of relatives had an increased lifetime morbid risk (vs those with alcoholism and those from the general population) for the proband's diagnosis. The SCZ and BP disorders were transmitted independently: only probands with manic disorders (BP or SA-BP subtype) showed increased familial risks of BP disorder, and only probands with prominent SCZ features (SCZ or SA) showed increased familial risks of SCZ disorder. However, SCZ probands had an increased familial risk for UP disorder (as did SA, BP, and UP probands) and for the SA-UP subtype. Aggregation of depression in families of SCZ probands could not be explained by the subtype of depression, broad or narrow definition of SCZ disorder, presence or absence of history of depression in SCZ probands, whether onset of depression in a relative occurred before or after onset of a proband's SCZ disorder, or assortative mating.These data suggest that there could be a familial relationship between the predispositions to schizophrenia and to major depression. We discuss a number of alternative hypotheses about the nature of this possible relationship.

THE IMPACT OF GENDER AND AGE AT ONSET ON THE FAMILIAL AGGREGATION OF SCHIZOPHRENIAEUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCEMaier, W., Lichtermann, D., Minges, J., Heun, R., Hallmayer, J.1993; 242 (5): 279-285

Abstract

Some recent family studies have shown that the familial risk for schizophrenia is higher in female than in male schizophrenics. It is debated whether the risks for the other disorders, such as schizotypal personality disorder or affective disorders in families of schizophrenics are similarly influenced by the proband's gender. Also, the reason for the effect of proband's gender on the recurrence risk for schizophrenia has not been clarified. This family study (159 probands, 589 first degree relatives) confirms that schizophrenia, but also schizophrenia spectrum disorders were more frequent in families of female compared with male schizophrenics. Neither age at onset in probands nor the interaction between gender and age at onset in probands had a relevant impact on the risk figures in relatives. Affective disorders occurred in families independently of the probands' gender. Aetiological heterogeneity or ascertainment bias may account for the modifying effect of proband's gender in schizophrenia.

Abstract

An excess concordance by sex among siblings affected with schizophrenia has been proposed by some previous and recent investigators. However, this hypothesis has not been supported by some recent studies having complete ascertainment of probands and relatives. The present report is based on sibships with multiple affected members derived from a family study of systematically recruited inpatients (146 probands with schizophrenia and 132 probands with other psychotic disorders). Evidence for an excess concordance rate for gender among proband-sibling pairs with both members affected is suggested under a broad definition of illness.

Abstract

This study investigated whether the distinction between schizoaffective disorder and affective disorders with mood-incongruent psychotic features as described in DSM-III-R is reflected by aggregation of schizophrenia in the families of probands with the former disorder and aggregation of affective disorders mainly among the relatives of probands with the latter type of disorders.The probands were 118 inpatients with definite lifetime diagnoses of DSM-III-R schizoaffective disorder or a major mood disorder with incongruent psychotic features according to structured clinical interviews. Diagnostic information on 475 of the probands' first-degree relatives was gathered through direct interviews (with 80% of the living first-degree relatives) or the family history approach. The rates of affective and psychotic disorders among these relatives were then compared with those among the relatives of a comparison group of 109 interviewed individuals from the general population who were matched on sociodemographic factors to the inpatient probands.With regard to the familial aggregation of schizophrenia, the DSM-III-R distinction emerged as valid. However, the risk of unipolar affective disorders was enhanced in the families of all of the subgroups of patients studied. The unipolar/bipolar distinction in both DSM-III-R diagnostic groups was reflected by distinct patterns of bipolar disorders in the relatives.The results partly support the DSM-III-R dichotomy of schizoaffective disorder and affective disorders with mood-incongruent psychotic features. Although the differences between these two diagnostic groups were significant, the magnitude of the differences remained relatively modest.

Abstract

Currently it is not clear whether minor forms of unipolar depression not matching the criteria of "major depression" should be considered as a separate diagnostic category. A controlled family study examined the familial aggregation of minor depression among probands with unipolar major depression. In the families of these probands the relative risk for minor depression was elevated by a similar magnitude to the risk for major depression. Therefore, the diagnostic category "minor depression" would not increase diagnostic sensitivity at the expense of diagnostic specificity as far as familiality is the criterion. In agreement with recent epidemiological studies, minor depression did not reveal a similar excess prevalence in females compared with males as major depression does. The variation of the sex ratio for any subtype of unipolar depression was not associated with the familiality of this disorder.

Abstract

Family, twin, and adoption studies suggest that genetic factors play an important role in the etiology of schizophrenia. Detection of single gene(s) involved in a higher susceptibility to a hereditary disease is possible with linkage analysis. The effects of serotonin2-receptor antagonists on symptoms of schizophrenia suggest that a mutation in the gene coding for this receptor subtype might be involved in the pathophysiology of this disease. Recently a copy DNA encoding the serotonin 5-HT2 receptor has been isolated and with a human 5-HT2 receptor copy DNA probe the HTR2 locus has been mapped to chromosome 13. Using multipoint linkage analysis between schizophrenia and genetic markers spanning the region of the HTR2 locus, we were able to exclude linkage between this candidate gene and schizophrenia in a Swedish kindred. Given this result, we conclude that the serotonin 5-HT2 receptor gene itself is not a major susceptibility gene for schizophrenia in this family.

Abstract

Ten pedigrees systematically ascertained in Germany were tested for linkage to chromosome 5q11-q13. In order to replicate the previous report by Sherrington et al (1988), families with a bipolar family member were omitted from the lod score calculations, all diagnoses were based upon Research Diagnostic Criteria, and four different models of the affection status were calculated, including the model for which Sherrington et al calculated the highest lod scores. None of the families investigated showed a positive lod score. Using multipoint linkage analyses, we were able to exclude the region for which a positive linkage has been reported.

Abstract

Late-onset depression (greater than or equal to 60 years) is believed to be less associated with a risk of depression in first-degree relatives than early-onset depression. However, family studies in elderly probands fitting the current methodological standards of family studies are not available. The reported family study in geriatric inpatients with unipolar major depression (n = 92) supported the proposed relationship between age at onset and the proposed familial loading. A comparison to families of age-matched controls (n = 33) revealed that relatives of probands with late-onset depression are still at an increased risk of depression. However, late-onset depression was not more common in families of probands with late-onset depression than in families of probands with early-onset depression. Besides the age at onset, the recurrence of depressive episodes defined distinct patterns of familial aggregation.

Abstract

The endogenous/non-endogenous distinction of unipolar major depression is widely accepted, as is the family study approach to the validation of diagnostic distinctions. Rates of affective disorders were examined in 689 first-degree relatives of 184 patients with unipolar major depression and were compared with 312 first-degree relatives of 80 healthy controls. Only unipolar depression and alcoholism were more common in families of depressed probands compared with families of healthy controls. As a variety of diagnostic definitions of endogenous depression have been proposed, probands and relatives were diagnosed in a polydiagnostic manner. None of the five diagnostic definitions of endogenous depression was able to identify patients with an increased familial risk of unipolar depression.

Abstract

Reversible cerebral ischemia was produced in anesthetized Mongolian gerbils by occluding both common carotid arteries. After 5 min of ischemia, brains were recirculated for 8 or 24 h. Treated animals received a single intraperitoneal injection of pentobarbital (50 mg/kg) immediately after the aneurysm clips were removed. At the end of the experiments, animals were reanesthetized and their brains frozen in situ. Tissue samples were taken from the cerebral cortex, lateral striatum, CA1 subfield of the hippocampus, thalamus, and cerebellum for measuring ornithine decarboxylase (ODC) activity and putrescine levels. In addition, 20-microns-thick coronal tissue sections were taken from the level of the striatum and stained with hematoxylin/eosin for evaluating the extent of ischemic neuronal necrosis in the lateral striatum. In control animals ODC activity and putrescine levels amounted, respectively, to 0.32 +/- 0.03 nmol/g/h and 10.2 +/- 0.5 nmol/g in the cerebral cortex; 0.34 +/- 0.02 nmol/g/h and 12.8 +/- 0.5 nmol/g in the lateral striatum; 0.58 +/- 0.05 nmol/g/h and 10.5 +/- 0.7 nmol/g in the hippocampal CA1 subfield; 0.35 +/- 0.01 nmol/g/h and 9.8 +/- 0.4 nmol/g in the thalamus; and 0.25 +/- 0.01 nmol/g/h and 8.3 +/- 0.6 nmol/g in the cerebellum. After 5 min cerebral ischemia and 8 h recirculation, a significant 7- to 16-fold increase in ODC activity was observed in all forebrain structures studied. Following 24 h recirculation, ODC activity normalized in the cortex, striatum, and thalamus but was still significantly above control values in the hippocampal CA1 subfield.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Brief periods of cerebral ischemia result in prolonged inhibition of protein synthesis. In CA1 sector of hippocampus inhibition is irreversible, leading to delayed death of pyramidal neurons. In order to study the possible role of gene transcription in this process, expression of four individual RNAs was investigated in the gerbil brain after 5 min of global cerebral ischemia by in situ hybridization with the following nucleic acid probes: plasmid pMr100 (ribosomal RNA sequences), plasma pAG82 (cytochrome c oxidase sequences), plasmid p629 (amyloid A4 precursor protein of Alzheimer's disease, pre-A4 protein), and plasmid pHF beta A-1 (beta-actin sequences). Cytochrome c oxidase mRNA and ribosomal RNA did not show any changes in expression up to 48 hr after ischemia. After longer recirculation times they gradually declined in the CA1 sector of hippocampus in parallel with the morphological manifestation of delayed neuronal death. The pre-A4 mRNA transiently decreased after 8 hr of recirculation of the CA1 sector but then recovered before it finally disappeared in parallel with delayed neuronal death. The beta-actin mRNA transiently appeared to increase after 8 hr of recirculation in the stratum radiatum of hippocampus but then also declined and disappeared when CA1 neurons began to disintegrate. The possible significance of these changes in the pathogenesis of ischemic neuronal damage is discussed.

Abstract

Reversible cerebral ischemia was produced in Mongolian gerbils by occluding both common carotid arteries. Following 5 min of ischemia brains were recirculated for 8, 24, or 96 hr. At the end of the experiments tissue samples were taken from the cerebral cortex and CA1 subfield of the hippocampus for measuring putrescine content and ornithine decarboxylase (ODC) activity. In 5 of 10 animals subjected to 96 hr of recirculation pentobarbital (50 mg/kg) was injected during early recirculation, and the density of ischemic cell damage was determined in the CA1 subfield of the hippocampus in treated and untreated animals. Reversible cerebral ischemia induced a drastic increase in ODC activity after 8 hr of recirculation (about 14-fold in the cortex and 7-fold in the hippocampus), which was markedly reduced following 24 hr of recirculation. Putrescine, in contrast, was high following 8 hr of recirculation and increased even further from 8 to 24 hr of recirculation. Postischemic pentobarbital treatment of animals significantly reduced both the increase in putrescine and the density of ischemic cell damage in the hippocampus. The results are discussed in view of the known activities of putrescine.

Abstract

The present series of experiments was designed to study regional profiles of polyamines (putrescine, spermidine, and spermine) in reversible cerebral ischemia produced in rats and Mongolian gerbils. Polyamine profiles did not change during ischemia, but did following recirculation. The most prominent changes were a dramatic postischemic increase in putrescine and a marked decrease in spermine in severely damaged regions. Within a given brain structure, the postischemic putrescine levels correlated closely with the density of ischemic cell injury and the time period of cerebral ischemia. Furthermore, putrescine was already considerably increased in the CA1-subfield of the hippocampus of gerbils after 8 h recirculation, i.e., at a time when the cells are still intact. The results indicate that putrescine may be viewed as an excellent biochemical correlate of ischemic cell injury. The postischemic changes in putrescine levels are discussed in relation to the known activities of this compound.

Abstract

Twenty mongolian gerbils were anesthetized (1.5% halothane) and severe forebrain ischemia was produced in 15 animals by occluding both common carotid arteries. After 5 min ischemia brains were recirculated spontaneously. Immediately after ischemia nimodipine (1.5 mg/kg) or pentobarbital (50 mg/kg) was injected intraperitoneally into five animals. Four days later animals were reanesthetized (1.5% halothane); the brains were frozen with liquid nitrogen and cut in a cryostat. Ten-micrometer-thick coronal cryostat sections were stained with cresyl violet to assess the extent of ischemic cell damage in the lateral striatum, the CA1-layer of the hippocampus, and the thalamus. In addition, tissue samples (about 4 mg each) were taken from the lateral striatum, CA1 layer of the hippocampus and the thalamus. Putrescine levels were measured in these samples using reversed-phase high performance liquid chromatography and fluorescence detection. Reversible cerebral ischemia produced a significant increase in putrescine in the lateral striatum (from 11.15 +/- 0.79 to 44.83 +/- 11.76 nmol/g, P less than or equal to 0.05), the CA1 subfield of the hippocampus (from 11.27 +/- 0.64 to 41.80 +/- 3.62 nmol/g, P less than or equal to 0.05) and less so in the thalamus (from 11.28 +/- 0.70 to 16.50 +/- 1.71 nmol/g).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Reversible cerebral ischemia was produced in Mongolian gerbils (Meriones unguiculatus) by occluding both common carotid arteries. After 5 min ischemia brains were recirculated for 8, 24, 48, 72, or 96 h. An additional 6 animals were subjected to 10 min ischemia and 24 h recirculation. Sham-operated animals served as controls. At the end of the experiments, brains were frozen in situ and cut in a cryostat. Coronal sections, 10 micron thick, were taken for histological staining. In addition, tissue samples (2-4 mg each) were taken from the cortex, lateral caudoputamen, CA1-layer of the hippocampus, and thalamus. Polyamines (spermidine, spermine, and the precursor putrescine) were measured in these samples using reverse-phase HPLC and fluorescence detection after extraction and precolumn derivatization. Five-minute cerebral ischemia had no effect on the levels of putrescine, spermidine, or spermine. However, following recirculation, putrescine increased markedly with time, being most pronounced in the CA1-subfield of the hippocampus, less so in the cortex, and even less so in the thalamus. After prolonged recirculation, severe neuronal necroses could be observed only in regions exhibiting high putrescine levels. Spermidine or spermine did not change during recirculation, except in severely damaged regions: Here, spermine levels were markedly reduced following prolonged recirculation. The post-ischemic increase in putrescine is discussed in respect to the known multiple activities of putrescine.

Abstract

Male Mongolian gerbils were subjected to bilateral carotid occlusion for 5 and 10 min, followed by 7 days of recirculation. After this interval, serial sections were made of the posterior region of the dorsal hippocampus, and the number of surviving neurons was determined per mm length of CA1 sector. In halothane-anesthetized animals only 21.1% of CA1 neurons survived 5-min ischemia, but this percentage could be raised to 78.6% when animals were pretreated with 25 mg/kg pentobarbital before ischemia. Pretreatment with 50 mg/kg pentobarbital before 5-min ischemia or pretreatment with 25 mg/kg pentobarbital before 10-min ischemia did not reduce CA1 lesions. It is concluded that a non-anesthetic dose of barbiturates is able to prevent selective vulnerability of CA1 sector, but that this effect is limited to the initial 5 min of ischemia.